WORLD INTELLECTUAL PROPERTY ORGANIZATION
International Bureau
PCT
INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT)
(51) International Patent Classification 6 :
C07D 498/18, A61K 31/445, 31/395 //
(C07D 498/18, 311;00, 221;00)
Al
(11) International Publication Number:
(43) International Publication Date:
WO 95/14023
26 May 1995 (26.05.95)
(21) International Application Number: PCT/US94/ 12777
(22) International Filing Date: 7 November 1994 (07.11.94)
(30) Priority Data:
08/155,064
08/327,391
19 November 1993 (19.1 1.93) US
26 October 1994 (26.10.94) US
(81) Designated States: CA, JP, European patent (AT, BE, CH, DE.
DK, ES, FR, GB, GR, IE, IT, LU, MC, NL, PT, SE).
Published
With international search report.
Before the expiration of the time limit for amending the
claims and to be republished in the event of the receipt of
amendments.
(71) Applicant: ABBOTT LABORATORIES [US/US]; CHAD
0377/AP6D-2, 100 Abbott Park Road, Abbott Park, IL
60064-3500 (US).
(72) Inventors: OR, Yat, Sun; 1 107 Wellington Avenue, Liber-
tyville, IL 60048 (US). LULY, Jay, R.; 1021 Mayfair, Lib-
ertyville, IL 60048 (US). WAGNER, Rolf; 6293 Old Farm
Lane, Gurnee, IL 60031 (US).
(74) Agents: CROWLEY, Steven, R. et al.; Abbott Laboratories,
Chad 0377/AP6D-2, 100 Abbott Park Road, Abbott Park,
IL 60064-3500 (US).
(54) Title: SEMISYNTHETIC ANALOGS OF RAPAMYCIN (MACROLIDES) BEING IMMUNOMODULATORS
(57) Abstract
Novel macrolide compounds, semisynthetic
analogs of Rapamycin, of formula (I) and pharma-
ceutically acceptable salts, esters, amides and pro-
drugs thereof, processes for the preparation of the
compounds of the invention, intermediates useful in
these processes, a pharmaceutical composition, and
a method of treating immunomodulatory disorders
are disclosed.
>
FOR THE PURPOSES OF INFORMATION ONLY
Codes used to identify States party to the PCT on the front pages of pamphlets publishing international
applications under the PCT.
AT
Austria
GB
United Kingdom
MR
Mauritania
AU
Australia
GE
Georgia
MW
Malawi
BB
Barbados
GN
Guinea
NE
Niger
BE
Belgium
GR
Greece
NL
Netherlands
BF
Burkina Faso
HU
Hungary
NO
Norway
BG
Bulgaria
IE
Ireland
NZ
New Zealand
BJ
Benin
IT
Italy
PL
Poland
BR
Brazil
JP
Japan
FT
Portugal
BY
Belarus
KE
Kenya
RO
Romania
CA
Canada
KG
Kyrgystan
RU
Russian Federation
CF
Central African Republic
KP
Democratic People's Republic
SD
Sudan
CG
Congo
of Korea
SE
Sweden
CH
Switzerland
KR
Republic of Korea
SI
Slovenia
CI
CSte d'lvoire
KZ
Kazakhstan
SK
Slovakia
CM
Cameroon
LI
Liechtenstein
SN
Senegal
CN
China
LK
Sri Lanka
TD
Chad
cs
Czechoslovakia
LU
Luxembourg
TG
Togo
cz
Czech Republic
LV
Latvia
TJ
Tajikistan
DE
Germany
MC
Monaco
TT
Trinidad and Tobago
DK
Denmark
MD
Republic of Moldova
UA
Ukraine
ES
Spain
MG
Madagascar
US
United States of America
FI
Finland
ML
Mali
uz
Uzbekistan
FR
France
MN
Mongolia
VN
Viet Nam
GA
Gabon
WO 95/14023
PCT/US94/12777
Semisynthetic analogs of Rapamycin (Macrolldes) being immunomodul ators
10 This is a continuation-in-part of U.S. patent application Serial No.
155,064, filed November 19, 1993.
Technical Field
The present invention relates to novel chemical compounds having
15 immunomodulatory activity and synthetic intermediates useful for the
preparation of the novel compounds, and in particular to macrolide
immunomodulators. More particularly, the invention relates to semisynthetic
analogs of rapamycin, means for their preparation, pharmaceutical compositions
containing such compounds and methods of treatment employing the same.
20
Background of the Invention
The compound cyclosporine (cyclosporin A) has found wide use since its
introduction in the fields of organ transplantation and immunomodulation, and
has brought about a significant increase in the success rate for transplantation
25 procedures. Recently, several classes of macrocyclic compounds having potent
immunomodulatory activity have been discovered. Okuhara et ai., in European
Patent Application No. 184,162, published June 11, 1986, disclose a number of
macrocyclic compounds isolated from the genus Streptomyces.
Immunosuppressant FK-506, isolated from a strain of S. tsukubaensis, is a
30 23-membered macrocyclic lactone represented by the formula shown below.
WO 95/14023
PCT/US94/12777
FK-506
5 Other related natural products, such as FR-900520 and FR-900523, which differ
from FK-506 in their alkyl substituent at C-21, have been isolated from S.
hygroscopicus yakushimnaensis. Yet another analog, FR-900525, produced by
S. tsukubaensis, differs from FK-506 in the replacement of a pipecolic acid
moiety with a proline group. Unsatisfactory side-effects associated with
10 cyclosporine and FK-506 such as nephrotoxicity, have led to a continued search
for immunosuppressant compounds having improved efficacy and safety.
Rapamycin is a macrocyclic triene antibiotic produced by Streptomyces
hygroscopicus, which was found to have antifungal activity, particularly against
Candida albicans, both in vitro and in vivo (C. Vezina et al., J. Antibiot. 1975,
15 28, 721; S. N. Sehgal et al., J. Antibiot. 1975, 28, 121; H. A. Baker et al., J.
Antibiot. 1978,57, 539; U.S. Patent No. 3,929,992; and U.S. Patent No.
3,993,749).
WO 95/14023
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-3-
Rapamycin
Rapamycin alone (U.S. Patent No. 4,885,171) or in combination with
5 picibanil (U.S. Patent No. 4,401,653) has been shown to have antitumor activity.
In 1977, rapamycin was also shown to be effective as an immunosuppressant in
the experimental allergic encephalomyelitis model, a model for multiple
sclerosis; in the adjuvant arthritis model, a model for rheumatoid arthritis; and
was shown to effectively inhibit the formation of IgE-like antibodies (R. Martel
10 et al., Can. J. Physiol. Pharmacol., 1977, 55, 48).
The immunosuppressive effects of rapamycin have also been disclosed in
FASEB, 1989, 3, 341 1 as has its ability to prolong survival time of organ grafts
in histoincompatible rodents (R. Morris, Med. Sci. Res., 1989, 77, 877). The
ability of rapamycin to inhibit T-cell activation was disclosed by M. Strauch
15 (FASEB, 1989, 3, 341 1). These and other biological effects of rapamycin are
reviewed in Transplantation Reviews, 1992, 6, 39-87.
Mono-ester and di-ester derivatives of rapamycin (esterification at
positions 31 and 42) have been shown to be useful as antifungal agents (U.S.
Patent No. 4,316,885) and as water soluble prodrugs of rapamycin (U.S. Patent
20 No. 4,650,803).
WO 95/14023
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-4-
Fermentation and purification of rapamcyin and 30-demethoxy
rapamycin have been described in the literature (C. Vezina et al. /. Antibiot.
(Tokyo), 1975, 28 (10), 721; S. N. Sehgal et aL, J. Antibiot. (Tokyo), 1975,
25(10), 727; 1983, 5(5(4), 351; N. L. Pavia et al., J. Natural Products, 1991,
5 54(1), 167-177).
Numerous chemical modifications of rapamycin have been attempted.
These include the preparation of mono- and di-ester derivatives of rapamycin
(WO 92/05179), 27-oximes of rapamycin (EPO 467606); 42-oxo analog of
rapamycin (U.S. Patent No. 5,023,262); bicyclic rapamycins (U.S. Patent No.
10 5,120,725); rapamycin dimers (U.S. Patent No. 5,120,727); silyl ethers of
rapamycin (U.S. Patent No. 5,120,842); and arylsulfonates and sulfamates (U.S.
Patent No. 5,177, 203). Rapamycin was recently synthesized in its naturally
occuring enantiomeric form (K. C. Nicolaou et al., J. Am. Chem. Soc, 1993, 775,
4419-4420; S. L. Schreiber, J. Am. Chem. Soc, 1993, 775, 7906-7907; S. J.
15 Danishefsky, J. Am. Chem. Soc, 1993, 775, 9345-9346.
It has been known that rapamycin, like FK-506, binds to FKBP-12
(Siekierka,'J. J.; Hung, S. H. Y.; Poe, M.; Lin, C. S.; Sigal, N. H. Nature, 1989,
341, 755-757; Harding, M. W.; Galat, A.; Uehling, D. E.; Schreiber, S. L. Nature
1989, 341, 758-760; Dumont, F. J.; Melino, M. R.; Staruch, M. J.; Koprak, S. L.;
20 Fischer, P. A.; Sigal, N. H. J. Immunol. 1990, 144, 1418-1424; Bierer, B. E.;
Schreiber, S. L.; Burakoff, S. J. Eur. J. Immunol. 1991, 21, 439-445; Fretz, H.;
Albers, M. W.; Galat, A.; Standaert, R. F.; Lane, W. S.; Burakoff, S. J.; Bierer,
B. E.; Schreiber, S. L. J. Am. Chem. Soc 1991, 775, 1409-1411). Recently it has
been discovered that the rapamycin/FKBP-12 complex binds to yet another
25 protein, which is distinct from calcineurin, the protein that the FK-506/FKBP-12
complex inhibits (Brown, E. J.; Albers, M. W.; Shin, T. B.; Ichikawa, K.; Keith,
C. T.; Lane, W. S.; Schreiber, S. L. Nature 1994, 369, 756-758.; Sabatini, D. M.;
Erdjument-Bromage, H.; Lui, M.; Tempest, P.; Snyder, S. H. Cell, 1994, 78, 35-
43).
30 Although some of these modified compounds exhibit immunosuppressive
activity, the need remains for macrocyclic immunosuppressants which do not
have the serious side effects frequently associated with immunosuppressant
therapy. Accordingly, one object of this invention is to provide novel
WO 95/14023
PCT/US94/12777
-5-
semisynthetic macrolides which possess the desired immunomodulatory activity
but which may be found to rninimize untoward side effects.
Another object of the present invention is to provide synthetic processes
for the preparation of such compounds from starting materials obtained by
5 fermentation, as well as chemical intermediates useful in such synthetic
processes.
A further object of the invention is to provide pharmaceutical
compositions containing, as an active ingredient, at least one of the above
compounds. Yet another object of the invention is to provide a method of
10 treating a variety of disease states, including post-transplant tissue rejection and
autoimmune disfunction.
Disclosure of the Invention
In one aspect of the present invention there are compounds of the formula
I
wherein R 1 is hydrogen, a hydroxy protecting group, loweralkyl or phenyl-
20 substituted loweralkyl;
R 2 is hydrogen and R 3 is hydroxy or protected hydroxy or R 2 and R 3 taken
together are oxo;
WO 95/14023
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-6-
R 4 is hydrogen or phenyl-substituted loweralkyl and R 5 is hydroxy or protected
hydroxy or R 5 is hydrogen or phenyl-substituted loweralkyl and R 4 is hydroxy or
protected hydroxy or R 4 and R 5 taken together are oxo;
5 R 6 is hydrogen or phenyl-substituted loweralkyl and R 7 is hydrogen, hydroxy or
protected hydroxy or R 7 is hydrogen or phenyl-substituted loweralkyl and R 6 is
hydroxy or protected hydroxy or R 6 and R 7 taken together are
(1) oxo,
(2) diazo,
10 (3) =CH 2
(4) -0-(CH 2 ) 2 -0-,
(5) -S-(CH 2 ) 2 -S-,
(6) -0-(CH 2 ) 3 -0-,
(7) -S-(CH 2 ) 3 -S-,
15 (8) =N-OR 20 wherein R 20 is hydrogen, loweralkyl, alkenyl, cycloalkyl,
cycloalkenyl, bicycloalkenyl, aryl, arylalkyl, heterocyclic or
heterocyclicalkyl, each of which is optionally substituted with loweralkyl,
halogen, hydroxy, aryl or heterocyclic; or
(9) =N-N(R21)(R22) wherein R 2 * and R 22 are independendy selected
20 from hydrogen, loweralkyl, aryl, arylalkyl, heterocyclic and
heterocyclicalkyl;
R 8 is hydrogen;
25 R9 is
(1) -OS(0) 2 CF 3 ,
(2) -OS(0) 2 F,
(3) -OS(0) 2 R 21a wherein R 21a is loweralkyl, aryl, arylalkyl, heterocyclic
or heterocyclicalkyl,
30 (4) -OC(0)R 23 wherein R 2 3 is loweralkyl, cycloalkyl, cycloalkylalkyl,
aryl, arylalkyl, heterocyclic, heterocyclicalkyl, alkoxy, -O-cycloalkyl,
-O-aryl, -O-heterocyclic, -O-(N-succinimidyl) or 5-tetrazolyl;
WO 95/14023
PCT/US94/12777
-7-
(5) -OC(0)-N(R 24 )(R 25 ) wherein R 24 and R 25 are independently selected
from
(a) hydrogen,
(b) loweralkyl,
5 (c) alkenyl,
(d) alkynyl,
(e) cycloalkyl,
(f) substituted loweralkyl, substituted alkenyl, substituted alkynyl
or substituted cycloalkyl wherein the loweralkyl group, the
10 alkenyl group, the alkynyl group or the cycloalkyl group is
substituted by one or two substituents independently selected
from
(i) hydroxy,
(ii) -COOH,
15 (iii) -CN,
(iv) -Q-loweralkyl, -Q-aryl, -Q-(arylalkyl), -Q-
heterocyclic or -Q-(heterocyclicalkyl) wherein Q is -O-,
-S-, -S(O)-, -S(0) 2 -, -C(O)-, -OC(O)-, -C(0)0-,
-C(0)C(0)-0-,
20 -0-C(0)C(0)-, -C(0)NH-, -NHC(O)-, -OC(0)NH-,
-NHC(0)0-, -NH-C(0)-NH-, -S(0) 2 NH-, -NHS(0) 2 -,
-NCR 2 ?)-, -C(NR 27 )NHNH- and -NHNHC(NR 27 )- wherein
R 27 is hydrogen, loweralkyl, aryl or heterocyclic,
(v) cycloalkyl,
25 (vi) aryl,
(vii) heterocyclic,
(viii) -N(R 28 )(R 29 ) wherein R 28 and R 29 are independently
selected from hydrogen, loweralkyl, hydroxyalkyl, aryl
and heterocyclic,
30 (ix) guanidino,
(x) -S(0) 2 R 11 wherein R 11 is loweralkyl, aryl or arylalkyl,
(xi) -OS(0) 2 R n wherein R 11 is defined as above,
(xii) -S0 3 H,
WO 95/14023
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-8-
(xiii) -S(0) 2 NH 2 ,
(xiv) -SR 2 & wherein R 2 ** is defined as above,
(xv) halogen,
(xvi) oxo and
5 (xvii) epoxy;
(g) aryl,
(h) heterocyclic,
(i) -NHC(0)-0-loweralkyl,
(j) -NHC(0)-aryl,
10 (k) -NHC(0)-heterocyclic and
(1) loweralkyl substituted by -OC(0)-R f wherein R f is
carboxyalkyl
or -N(R 24 )(R 25 ) taken together form a nitrogen-containing
heterocyclic group,
15 (6) -OR 25 wherein R 25 is as defined above,
(7) a protected hydroxy group,
(8) -OC(0)N(OR 24 )(R 2 5) wherein R 24 and R 2 $ are defined as above,
(9) -0(CH 2 )jC(0)OR 20 wherein i is one or two and R 20 is independently
defined as above,
20 (10) -O(CH(Si(CH 3 ) 3 ))-(CH 2 ) j C(O)OR 2 0 wherein j is zero or one and
R 20 is independently defined as above,
(11) -0(CH 2 )jC(0)N(R24)(R25) wherein i, R 24 and R 2 $ are defined as
above,
(12) -0(CH 2 ) i C(0)N(OR 24 )(R 2 5) wherein i, R 24 and R 2 5 are defined as
25 above,
(13) -0(CH 2 ) i C(0)N(R24)(N(R 24 )(R25)) wherein i, R 24 and R 2 5 are
defined as above,
(14) -0(CH 2 )jNHC(0)N(R 24 )(R 2 5) wherein i, R 24 and R 2 5 are defined as
above,
30 (15) -0(CH 2 ) i NHC(0)N(OR 24 )(R 2 5) wherein i, R 24 and R 2 5 are defined
as above,
(16) -0(CH 2 ) i NHC(0)N(R 24 )(N(R 24 )(R 2 5)) wherein i, R 24 and R 2 5 are
defined as above,
WO 95/14023
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-9-
(17) -OS(0) 2 N(R24)(R25) wherein R24 and R25 are defined as above,
(18) -0(CH 2 ) r NHC(0)R24 wherein R2 4 i s defined as above,
(19) -OCH(R24)-SH wherein R24 i s defined as above,
(20) -OCH(R24)-S-loweralkyl wherein R24 i s defined as above,
5 (21) -OCH(R24)-S-aryl wherein R24 i s defined as above and
(22) -N 3 ;
RlOa i s hydrogen and RiOb i s hydrogen, hydroxy, protected hydroxy, alkoxy,
alkenyl, alkenyloxy, halogen or -SR28 wherein R 2 8 i s independendy defined as
10 above or R 10b is hydrogen and R 10a is hydrogen, hydroxy, protected hydroxy,
alkoxy, alkenyl, alkenyloxy, halogen or -SR28 wherein R28 i s independently
defined as above or RiOa anc i RlOb gj-g b ot h a ik oxy or -SR 2 8a wherein R 28 a i s
loweralkyl, aryl or heterocyclic or R l( & and R 10b taken together are oxo; and
15 X is hydrogen and Y is hydrogen, hydroxy or protected hydroxy or Y is hydrogen
and X is hydroxy or protected hydroxy or X and Y taken together are oxo;
or a pharmaceutically acceptable salt, ester, amide or prodrug thereof.
Preferred compounds of the formula I are those wherein:
R 1 is methyl;
R 2 is hydrogen and R 3 is hydroxy;
25 R 4 is hydrogen and R 5 is hydroxy or R5 is hydrogen and R 4 is hydroxy or R 4 and
R 5 taken together are oxo;
R 6 and R 7 are defined as above;
R 8 is hydrogen;
R 9 is defined as above;
30 R!0a i s hydrogen, methoxy or fluoro and R*0b is hydrogen; and
X and Y taken together are oxo.
WO 95/14023
PCT/US94/12777
-10-
More preferred compounds of the formula I are those wherein:
R 1 is methyl;
R 2 is hydrogen and R 3 is hydroxy;
R 4 is hydrogen and R 5 is hydroxy or R 5 is hydrogen and R 4 is hydroxy or R 4 and
5 R 5 taken together are oxo;
R 6 and R 7 taken together are
(1) oxo,
(2) =N-OR 20 wherein R 20 is hydrogen, loweralkyl, alkenyl, cycloalkyl,
cycloalkenyl, bicycloalkenyl, aryl, arylalkyl, heterocyclic or
10 heterocyclicalkyl, each of which is optionally substituted with loweralkyl,
halogen, hydroxy, aryl or heterocyclic; or
(3) =N-N(R 21 )(R 22 ) wherein R 21 and R 22 are independently selected
from hydrogen, loweralkyl, aryl, arylalkyl, heterocyclic and
heterocyclicalkyl;
15 R 8 is hydrogen;
R9is
(1) -OH,
(2) -OC(0)R 23 wherein R23 i s -O-aryl, -O-(N-succinimidyl), -O-
benzotriazolyl, -0-2'-pyridyl or 5-tetrazolyl,
20 (3) -OC(0)-N(R 24 )(R 2 5) wherein R 24 and R 2 5 are independently selected
from
(a) hydrogen,
(b) loweralkyl,
(c) alkenyl,
25 (d) alkynyl,
(e) cycloalkyl,
(f) substituted loweralkyl, substituted alkenyl, substituted alkynyl
or substituted cycloalkyl wherein the loweralkyl group, the
alkenyl group, the alkynyl group or the cycloalkyl group is
30 substituted by one or two substituents independently selected from
(i) hydroxy,
(ii) -COOH,
(iii) -CN,
95/14023
PCT/US94/12777
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(iv) -Q-loweralkyl, -Q-aryl, -Q-(arylalkyl), -Q-heterocyclic
or -Q-(heterocyclicalkyl) wherein Q is -O-, -S-, -S(O)-,
-S(0) r , -C(O)-, -OC(O)-, -C(0)0-, -C(0)C(0)-0-,
-0-C(0)C(0)-, -C(0)NH-, -NHC(O)-, -OC(0)NH-,
-NHC(0)0-, -NH-C(0)-NH-, -S(0) 2 NH-, -NHS(0) 2 -,
-N(R27)., -C(NR27)NHNH_ an d -NHNHC(NR27). wherein
R 27 is hydrogen, loweralkyl, aryl or heterocyclic,
(v) cycloalkyl,
(vi) aryl,
(vii) heterocyclic,
(viii) -N(R28)(R29) wherein R28 and R29 are independently
selected from hydrogen, loweralkyl, hydroxyalkyl, aryl
and heterocyclic,
(ix) guanidino,
(x) -S(0) 2 R n wherein R 11 is loweralkyl, aryl or arylalkyl,
(xi) -OSCO^R 11 wherein RH is defined as above,
(xii) -SO3H,
(xiii) -S(0) 2 NH 2 ,
(xiv) -SR28 wherein R 2 8 i s defined as above,
(xv) halogen,
(xvi) oxo and
(xvii) epoxy;
(g) aryl,
(h) heterocyclic,
(i) -NHC(0)-0-loweralkyl,
(j) -NHC(0)-aryl,
(k) -NHC(0)-heterocyclic and
(1) loweralkyl substituted by -OC(0)-R f wherein R f is
carboxyalkyl
or -N(R 24 )(R25) taken together form a nitrogen-containing
heterocyclic group,
(4) -OC(0)N(OR24)( R 25) wherein R24 and R 25 ^ defined as above,
(5) -0(CH 2 ) i C(0)N(R24)(R25 ) whe rein iis one or two and R24 an d R25
are defined as above,
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(6) -0(CH 2 ) i C(0)N(OR 24 )(R 25 ) wherein i, R 24 and R 25 are defined as
above,
(7) -0(CH 2 ) i NHC(0)N(R 24 )(R 2 5) wherein i, R 24 and R 25 are defined as
above or
5 (8) -0(CH 2 ) i NHC(0)N(OR 24 )(R25) wherein i, R 24 and R 2 5 are defined
as above;
RlOa i s hydrogen, methoxy or fluoro and R 10b is hydrogen; and
X and Y taken together are oxo.
10 Even more preferred compounds of the formula I are those wherein:
R 1 is methyl;
R 2 is hydrogen and R 3 is hydroxy;
R 4 and R 5 taken together are oxo;
R 6 and R 7 taken together are
15 (1) oxo,
(2) =N-OR 20 wherein R 20 is hydrogen, loweralkyl, alkenyl, cycloalkyl,
cycloalkenyl, bicycloalkenyl, aryl, arylalkyl, heterocyclic or
heterocyclicalkyl, each of which is optionally substituted with loweralkyl,
halogen, hydroxy, aryl or heterocyclic; or
20 (3) =N-N(R 2 1)(R 22 ) wherein R 21 and R 22 are independentiy selected
from hydrogen, loweralkyl, aryl, arylalkyl, heterocyclic and
heterocyclicalkyl;
R 8 is hydrogen;
R9is
25 (1) -OH,
(2) -OC(0)R 23 wherein R 23 is -O-aryl, -O-(N-succinimidyl), -O-
benzotriazolyl, -0-2'-pyridyl or 5-tetrazolyl,
(3) -OC(0)-N(R 24 )(R 2 5) wherein R 24 and R25 are independently selected
from
30 (a) hydrogen,
(b) loweralkyl,
(c) alkenyl,
(d) alkynyl,
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10
-13-
(e) cycloalkyl,
(f) substituted loweralkyl, substituted alkenyl, substituted alkynyl
or substituted cycloalkyl wherein the loweralkyl group, the
alkenyl group, the alkynyl group or the cycloalkyl group is
substituted by one or two substituents independently selected from
(i) hydroxy,
(ii) -COOH,
(iii) -CN,
(iv) -Q-loweralkyl, -Q-aryl, -Q-(arylalkyl), -Q-heterocyclic
or -Q-(heterocyclicalkyl) wherein Q is -O-, -S-, -S(6)-,
-S(0) 2 -, -C(O)-, -OC(O)-, -C(0)0-, -C(0)C(0)-0-,
-0-C(0)C(0)-, -C(0)NH-, -NHC(O)-, -OC(0)NH-,
-NHC(0)0-, -NH-C(0)-NH-, -S(0) 2 NH-, -NHS(0) 2 -,
-N(R27)_, -C(NR27)NHNH- and -NHNHC(NR27). wherein
15 R 27 is hydrogen, loweralkyl, aryl or heterocyclic,
(v) cycloalkyl,
(vi) aryl,
(vii) heterocyclic,
(viii) -N(R28)( R 29) wherein R28 an d R29 are independently
20 selected from hydrogen, loweralkyl, hydroxyalkyl, aryl
and heterocyclic,
(ix) guanidino,
(x) -S(0) 2 R u wherein R 11 is loweralkyl, aryl or arylalkyl,
(xi) -OS(0) 2 RH wherein RH is defined as above,
25 (xii) -S0 3 H,
(xiii) -S(0) 2 NH 2 ,
(xiv) -SR28 wherein R 2 8 i s defined as above,
(xv) halogen,
(xvi) oxo and
30 (xvii) epoxy;
(g) aryl,
(h) heterocyclic,
(i) -NHC(0)-0-Ioweralkyl,
(j) -NHC(0)-aryl,
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(k) -NHC(0)-heterocyclic and
(1) loweralkyl substituted by -OC(0)-R f wherein R f is
carboxyalkyl
or -NCR 24 )^ 25 ) taken together form a nitrogen-containing
5 heterocyclic group,
(4) -OC(0)N(OR 24 )(R 2 5) wherein R 24 and R 2 * are defined as above,
(5) -0(CH 2 ) i C(0)N(R24)(R25) wherein iis one or two and R 24 and R 2 5
are defined as above,
(6) -0(CH 2 ) i C(0)N(OR 2 4)(R25) wherein i, R24 and R 2 5 are defined as
10 above,
(7) -0(CH 2 ) i NHC(0)N(R24)(R25) wherein i, R 24 and R 2 $ are defined as
above or
(8) -0(CH 2 ) i NHC(0)N(OR 24 )(R 2 5) wherein i, R 24 and R25 are defined as
above;
15 R!0a is methoxy and R 1 ^ is hydrogen; and
X and Y taken together are oxo.
Most preferred compounds of the formula I are those wherein:
R 1 is methyl;
20 R 2 is hydrogen and R 3 is hydroxy;
R 4 and R 5 taken together are oxo;
R 6 and R 7 taken together are oxo;
R 8 is hydrogen;
R 9 is -OH, -O-loweralkyl or -OC(0)N(R 24 )(R 2 5) wherein R 24 and R 2 5 are
25 defined as above;
R 10a is methoxy and R 10b is hydrogen; and
X and Y taken together are oxo.
30
WO 95/14023
PCT/US94/12777
-15-
In fnother aspect of the present invention there are compounds of the
formula II:
n
5 wherein R 1 is hydrogen, a hydroxy protecting group, loweralkyl or phenyl-
substituted loweralkyl;
R 2 is hydrogen and R 3 is hydroxy or protected hydroxy or R 2 and R 3 taken
together are oxo;
R 4 is hydrogen or phenyl-substituted loweralkyl and R 5 is hydroxy or protected
hydroxy or R 5 is hydrogen or phenyl-substituted loweralkyl and R 4 is hydroxy or
protected hydroxy or R 4 and R 5 taken together are oxo;
15 R 6 is hydrogen or phenyl-substituted loweralkyl and R 7 is hydrogen, hydroxy or
protected hydroxy or R 7 is hydrogen or phenyl-substituted loweralkyl and R 6 is
hydroxy or protected hydroxy or R 6 and R 7 taken together are
(1) oxo,
(2) diazo,
20 (3) =CH 2
(4) -0-(CH 2 ) 2 -0-,
(5) -S-(CH 2 ) 2 -S-,
(6) -0-(CH 2 ) 3 -0-,
(7) -S-(CH 2 ) 3 -S-,
WO 95/14023
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-16-
(8) =N-OR 20 wherein R 20 is hydrogen, loweralkyl, alkenyl, cycloalkyl,
cycloalkenyl, bicycloalkenyl, aryl, arylalkyl, heterocyclic or
heterocyclicalkyl, each of which is optionally substituted with loweralkyl,
halogen, hydroxy, aryl or heterocyclic; or
5 (9) =N-N(R 21 )(R22) wherein R 21 and R 22 are independently selected
from hydrogen, loweralkyl, aryl, arylalkyl, heterocyclic and
heterocyclicalkyl;
R 8 is hydrogen;
10
R^is
(l)-SR 24 wherein R 24 is
(a) hydrogen,
(b) loweralkyl,
15 (c) alkenyl,
(d) alkynyl,
(e) cycloalkyl,
(f) substituted loweralkyl, substituted alkenyl, substituted alkynyl
or substituted cycloalkyl wherein the loweralkyl group, the
20 alkenyl group, the alkynyl group or the cycloalkyl group is
substituted by one or two substituents independently selected from
(i) hydroxy,
(ii) -COOH,
(iii) -CN,
25 (iv) -Q-loweralkyl, -Q-aryl, -Q-(arylalkyl), -Q-heterocyclic
or -Q-(heterocyclicalkyl) wherein Q is -O-, -S-, -S(O)-,
-S(0) 2 -, -C(O)-, -OC(O)-, -C(0)0-, -C(0)C(0)-0-,
-0-C(0)C(0)-, -C(0)NH-, -NHC(O)-, -OC(0)NH-,
-NHC(0)0-, -NH-C(0)-NH-, -S(0) 2 NH-, -NHS(0) 2 -,
30 -N(R 27 )-, -C(NR 27 )NHNH- and -NHNHC(NR 27 )- wherein
R 27 is hydrogen, loweralkyl, aryl or heterocyclic,
(v) cycloalkyl,
(vi) aryl,
WO 95/14023
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-17-
(vii) heterocyclic,
(viii) -N(R 28 )(R 29 ) wherein R 28 and R 29 are independently
selected from hydrogen, loweralkyl, hydroxyalkyl, aryl
and heterocyclic,
5 (ix) guanidino,
(x) -S(0) 2 R 11 wherein R 11 is loweralkyl, aryl or arylalkyl,
(xi) -OSCO^R 11 wherein R 11 is defined as above,
(xii) -S0 3 H,
(xiii) -S(0) 2 NH 2 ,
10 (xiv) -SR 28 wherein R 28 is defined as above,
(xv) halogen,
(xvi) oxo and
(xvii) epoxy;
(g) aryl,
15 (h) heterocyclic,
(i) -C(0)-0-loweralkyl,
(j) -C(0)-aryl,
(k) -C(0)-heterocyclic or
(1) loweralkyl substituted by -OC(0)-R f wherein R f is
20 carboxyalkyl,
(2) -SC(=NH)-NH 2 ,
(3) -SC(=N-NH 2 )-NH 2 ,
(4) -Se-phenyl or
(5) -Se(0)-phenyl;
25
RlOa i s hydrogen and R 10b is hydrogen, hydroxy, protected hydroxy, alkoxy,
alkenyl, alkenyloxy, halogen or -SR 28 wherein R 28 is independently defined as
above or R J 0b i s hydrogen and R 10a is hydrogen, hydroxy, protected hydroxy,
alkoxy, alkenyl, alkenyloxy, halogen or -SR 28 wherein R 28 is independently
30 defined as above or R 10a and R 1Q b are both alkoxy or -SR 28a wherein R 28a is
loweralkyl, aryl or heterocyclic or R*0a and RiOb taken together are oxo; and
X is hydrogen and Y is hydrogen, hydroxy or protected hydroxy or Y is hydrogen
and X is hydroxy or protected hydroxy or X and Y taken togehter are oxo;
WO 95/14023
PCT/US94/12777
-18-
or a pharmaceutically acceptable salt, ester, amide or prodrug thereof.
5 Preferred compounds of the formula II are those wherein:
R 1 is methyl;
R 2 is hydrogen and R 3 is hydroxy;
R 4 is hydrogen and R 5 is hydroxy or R 5 is hydrogen and R 4 is hydroxy or R 4 and
R 5 taken together are oxo;
10 R 6 and R 7 are defined as above;
R 8 is hydrogen;
R 9 is -SR 24 wherein R 24 is defined as above;
RlOa i s hydrogen, methoxy or fluoro and R 10b is hydrogen; and
X and Y taken together are oxo.
15
More preferred compounds of the formula II are those wherein:
R 1 is methyl;
R 2 is hydrogen and R 3 is hydroxy;
R 4 is hydrogen and R 5 is hydroxy or R 5 is hydrogen and R 4 is hydroxy or R 4 and
20 R 5 taken together are oxo;
R 6 and R 7 taken together are
(1) oxo,
(2) =N-OR 2 0 wherein R 2 ^ is hydrogen, loweralkyl, alkenyl, cycloalkyl,
cycloalkenyl, bicycloalkenyl, aryl, arylalkyl, heterocyclic or
25 heterocyclicalkyl, each of which is optionally substituted with loweralkyl,
halogen, hydroxy, aryl or heterocyclic; or
(3) =N-N(R 21 )(R 22 ) wherein R 21 and R 22 are independently selected
from hydrogen, loweralkyl, aryl, arylalkyl, heterocyclic and
heterocyclicalkyl;
30 R 8 is hydrogen;
R 9 is -SR 24 wherein R 24 is hydrogen, loweralkyl, substituted loweralkyl as
defined above, aryl or heterocyclic;
RlOa i s hydrogen, methoxy or fluoro and R 10b is hydrogen; and
X and Y taken together are oxo.
WO 95/14023
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-19-
Even more preferred compounds of the formula II are those wherein:
R 1 is methyl;
R 2 is hydrogen and R 3 is hydroxy;
5 R 4 and R5 taken together are oxo;
R 6 and R 7 taken together are oxo;
R 8 is hydrogen;
R 9 is -SR 24 wherein R 24 is hydrogen, loweralkyl, substituted loweralkyl as
defined above, aryl or heterocyclic;
10 R!0a i s methoxy and R 10b is hydrogen; and
X and Y taken together are oxo.
Most preferred compounds of the formula II are those wherein:
R 1 is methyl;
15 R 2 is hydrogen and R 3 is hydroxy;
R 4 and R 5 taken together are oxo;
R 6 and R 7 taken together are oxo;
R 8 is hydrogen;
R 9 is -SR 24 wherein R 24 is hydrogen, imidazol-2-yl or N-methyl-imidazol-2-yl;
20 R!0a i s methoxy and R 10b is hydrogen; and
X and Y taken together are oxo.
In another aspect of the present invention there are compounds of the
formula HI:
25
ni
WO 95/14023
PCT/US94/12777
-20-
wherein R 1 is hydrogen, a hydroxy protecting group, loweralkyl or phenyl-
substituted loweralkyl;
R 2 is hydrogen and R 3 is hydroxy or protected hydroxy or R 2 and R 3 taken
5 together are oxo;
R 4 is hydrogen or phenyl-substituted loweralkyl and R 5 is hydroxy or protected
hydroxy or R 5 is hydrogen or phenyl-substituted loweralkyl and R 4 is hydroxy or
protected hydroxy or R 4 and R 5 taken together are oxo;
10
R 6 is hydrogen or phenyl-substituted loweralkyl and R 7 is hydrogen, hydroxy or
protected hydroxy or R 7 is hydrogen or phenyl-substituted loweralkyl and R 6 is
hydroxy or protected hydroxy or R 6 and R 7 taken together are
(1) oxo,
15 (2) diazo,
(3) =CH 2
(4) -0-(CH 2 ) 2 -0-,
(5) -S-(CH 2 ) 2 -S-,
(6) -0-(CH 2 ) 3 -0-,
20 (7) -S-(CH 2 ) 3 -S-,
(8) =N-OR 20 wherein R 20 is hydrogen, loweralkyl, alkenyl, cycloalkyl,
cycloalkenyl, bicycloalkenyl, aryl, arylalkyl, heterocyclic or
heterocyclicalkyl, each of which is optionally substituted with loweralkyl,
halogen, hydroxy, aryl or heterocyclic; or
25 (9) =N-N(R 2 1)(R 22 ) wherein R 2 1 and R 22 are independently selected
from hydrogen, loweralkyl, aryl, arylalkyl, heterocyclic and
heterocyclicalkyl;
R 8 is hydrogen;
30
R^is
(1) -N(R 24 )(R 2 5) wherein R 24 and R 2 5 are independendy selected from
(a) hydrogen,
WO 95/14023
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-21-
(b) loweralkyl,
(c) alkenyl,
(d) alkynyl,
(e) cycloalkyl,
5 (f) substituted loweralkyl, substituted alkenyl, substituted alkynyl
or substituted cycloalkyl wherein the loweralkyl group, the
alkenyl group, the alkynyl group or the cycloalkyl group is
substituted by one or two substituents independently selected from
(i) hydroxy,
10 (ii) -COOH,
(iii) -CN,
(iv) -Q-loweralkyl, -Q-aryl, -Q-(arylalkyl), -Q-heterocyclic
or -Q-(heterocyclicalkyl) wherein Q is -O-, -S-, -S(O)-,
-S(0) 2 -, -C(O)-, -OC(O)-, -C(0)0-, -C(0)C(0)-0-,
15 -0-C(0)C(0)-, -C(0)NH-, -NHC(O)-, -OC(0)NH-,
-NHC(0)0-, -NH-C(0)-NH-, -S(0) 2 NH-, -NHS(0) 2 -,
-N(R27). ? -C(NR27)NHNH- and -NHNHC(NR27). wherein
R 27 is hydrogen, loweralkyl, aryl or heterocyclic,
(v) cycloalkyl,
20 (vi) aryl,
(vii) heterocyclic,
(viii) -N(R28)( R 29) wherein R28 an d R29 are independently
selected from hydrogen, loweralkyl, hydroxyalkyl, aryl
and heterocyclic,
15 (ix) guanidino,
(x) -S(0) 2 RH wherein is loweralkyl, aryl or arylalkyl,
(xi) -OS(0) 2 Rll wherein R 11 is defined as above,
(xii) -S0 3 H,
(xiii) -S(0) 2 NH 2 ,
0 (xiv) -SR28 wherein R28 i s defined as above,
(xv) halogen,
(xvi) oxo and
(xvii) epoxy;
(g) aryl,
WO 95/14023
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-22-
(h) heterocyclic,
(i) -NHC(0)-0-loweralkyl,
G) -NHC(0)-aryl,
(k) -NHC(0)-heterocyclic and
5 (1) loweralkyl substituted by -OC(0)-R f wherein R f is
carboxyalkyl,
(2) -N=C=0,
(3) -NHC(0)-R* or
(4) -NHS(0)2-R* wherein R* is
10 (a) loweralkyl,
(b) cycloalkyl,
(c) aryl,
(d) heterocyclic,
(e) loweralkyl substituted by one or two substituents
15 independently selected from
(i) hydroxy,
(ii) -COOH,
(iii) -CN,
(iv) -Q-loweralkyl, -Q-aryl, -Q-(arylalkyl), -Q-heterocyclic
20 or -Q-(heterocyclicalkyl) wherein Q is -O-, -S-, -S(O)-,
-S(0) 2 -, -C(O)-, -OC(O)-, -C(0)0-, -C(0)C(0)-0-,
-0-C(0)C(0)-, -C(0)NH-, -NHC(O)-, -OC(0)NH-,
-NHC(0)0-, -NH-C(0)-NH-, -S(0) 2 NH-, -NHS(0) 2 -,
-N(R 27 )-, -C(NR 2 7)NHNH- and -NHNHC(NR 27 )- wherein
25 R 27 is hydrogen, loweralkyl, aryl or heterocyclic,
(v) cycloalkyl,
(vi) aryl,
(vii) heterocyclic,
(viii) -N(R 28 )(R 29 ) wherein R 28 and R 29 are independently
30 selected from hydrogen, loweralkyl, hydroxyalkyl, aryl
and heterocyclic,
(ix) guanidino,
(x) -SCO^R 11 wherein R 11 is loweralkyl, aryl or arylalkyl,
(xi) -OSCO^R 11 wherein R 11 is defined as above,
WO 95/14023
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-23-
(xii) -SO3H,
(xiii) -S(0) 2 NH 2 ,
(xiv) -SR 28 wherein R 28 is defined as above,
(xv) halogen,
(xvi) oxo and
(xvii) epoxy;
(f) -N(R a )(R b ) wherein R a and R b are independently selected from
hydrogen, loweralkyl and -N(R c )(R d ) wherein R c and R d are
independently selected from hydrogen and loweralkyl or
(g) -OR* wherein R* is defined as above;
RlOa i s hydrogen and R 10b is hydrogen, hydroxy, protected hydroxy, alkoxy,
alkenyl, alkenyloxy, halogen or -SR 28 wherein R 28 is independently defined as
above or R 10b is hydrogen and R 10a is hydrogen, hydroxy, protected hydroxy,
alkoxy, alkenyl, alkenyloxy, halogen or -SR 28 wherein R 28 is independently
defined as above or R 10a and R 10b are both alkoxy or -SR 28a wherein R 28a is
loweralkyl, aryl or heterocyclic or R 10a and R 10b taken together are oxo; and
X is hydrogen and Y is hydrogen, hydroxy or protected hydroxy or Y is hydrogen
and X is hydroxy or protected hydroxy or X and Y taken togehter are oxo;
or a pharmaceutically acceptable salt, ester, amide or prodrug thereof.
Preferred compounds of the formula III are those wherein:
R 1 is methyl;
R 2 is hydrogen and R 3 is hydroxy;
R 4 is hydrogen and R 5 is hydroxy or R^ is hydrogen and R 4 is hydroxy or R 4 and
R 5 taken together are oxo;
R6 and R 7 are defined as above;
R 8 is hydrogen;
R 9 is -N(R 24 )(R 25 ) wherein R 24 and R 25 are defined as above;
RlOa j s hydrogen, methoxy or fluoro and R 10b is hydrogen; and
WO 95/14023
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-24-
X and Y taken together are oxo.
More preferred compounds of the formula HI are those wherein:
R 1 is methyl;
5 R 2 is hydrogen and R 3 is hydroxy;
R 4 is hydrogen and R 5 is hydroxy or R 5 is hydrogen and R 4 is hydroxy or R 4 and
R 5 taken together are oxo;
R 6 and R 7 taken together are
(1) oxo,
10 (2) =N-OR 20 wherein R 20 is hydrogen, loweralkyl, alkenyl, cycloalkyl,
cycloalkenyl, bicycloalkenyl, aryl, arylalkyl, heterocyclic or
heterocyclicalkyl, each of which is optionally substituted with loweralkyl,
halogen, hydroxy, aryl or heterocyclic; or
(3) =N-N(R 21 )(R 22 ) wherein R 21 and R 22 are independently selected
15 from hydrogen, loweralkyl, aryl, arylalkyl, heterocyclic and
heterocyclicalkyl;
R 8 is hydrogen;
R 9 is -N(R 24 )(R 25 ) wherein R 24 and R 25 are independently selected from
hydrogen, loweralkyl, substituted loweralkyl as defined above,
20 -NHC(0)-0-loweralkyl, -NHC(0)-aryl and -NHC(0)-heterocyclic or R 24 and
R 25 taken together form a heterocyclic ring;
R 10a is hydrogen, methoxy or fluoro and R 10b is hydrogen; and
X and Y taken together are oxo.
25 Even more preferred compounds of the formula III are those wherein:
R 1 is methyl;
R 2 is hydrogen and R 3 is hydroxy;
R 4 and R 5 taken together are oxo;
R 6 and R 7 taken together are oxo;
30 R 8 is hydrogen;
R 9 is -N(R 24 )(R 25 ) wherein R 24 and R 25 are independently selected from
hydrogen, loweralkyl, substituted loweralkyl as defined above,
-NHC(0)-0-loweralkyl„ -NHC(0)-aryl and -NHC(0)-heterocyclic or R 24 and
R 25 taken together form a heterocyclic ring;
WO 95/14023
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-25-
R 10a is methoxy and R 10b is hydrogen; and .
X and Y taken together are oxo.
Most preferred compounds of the formula III are those wherein:
5 R 1 is methyl;
R 2 is hydrogen and R 3 is hydroxy;
R 4 and R 5 taken together are oxo;
R 6 and R 7 taken together are oxo;
R 8 is hydrogen;
10 R 9 is -NH 2 , 2-pyridon-l-yl or 4-pyridon-l-yl;
R 10a is methoxy and R 10b is hydrogen; and
X and Y taken together are oxo.
In another aspect of the present invention there are compounds of the
formula IV:
WO 95/14023
PCT/US94/12777
.(d) H ;
10
R 1 is hydrogen, a hydroxy protecting group, loweralkyl or phenyl-substituted
loweralkyl;
R 2 is hydrogen and R 3 is hydroxy or protected hydroxy or R 2 and R 3 taken
15 together are oxo;
R 4 is hydrogen or phenyl-substituted loweralkyl and R 5 is hydroxy or protected
hydroxy or R 5 is hydrogen or phenyl-substituted loweralkyl and R 4 is hydroxy or
protected hydroxy or R 4 and R 5 taken together are oxo;
20
R 6 is hydrogen or phenyl-substituted loweralkyl and R 7 is hydrogen, hydroxy or
protected hydroxy or R 7 is hydrogen or phenyl-substituted loweralkyl and R 6 is
hydroxy or protected hydroxy or R 6 and R 7 taken together are
(1) oxo,
25 (2) diazo,
(3) =CH 2
WO 95/14023
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-27-
(4) -0-(CH 2 ) 2 -0-,
(5) -S-(CH 2 ) 2 -S-,
(6) -0-(CH 2 ) 3 -0-,
(7) -S-(CH 2 ) 3 -S-,
(8) =N-OR 20 wherein R 20 is hydrogen, loweraikyl, alkenyl, cycloalkyl,
cycloalkenyl, bicycloalkenyl, aryl, arylalkyl, heterocyclic or
heterocyclicalkyl, each of which is optionally substituted with loweraikyl,
halogen, hydroxy, aryl or heterocyclic; or
(9) =N-N(R 21 )(R 22 ) wherein R 21 and R 22 are independently selected
from hydrogen, loweraikyl, aryl, arylalkyl, heterocyclic and
heterocyclicalkyl;
R 8 , R 9 , R 18 and R 19 are independently selected from
(1) hydrogen,
(2) -OS(0) 2 CF 3 ,
(3) -OS(0) 2 F,
(4) -OS(0) 2 R 21a wherein R 21a is loweraikyl, aryl, arylalkyl, heterocyclic
or heterocyclicalkyl,
(5) -OC(0)R 23 wherein R 2 3 is -O-aryl, -O-(N-succinimidyl),
-O-benzotriazolyl, -0-2'-pyridyl or 5-tetrazolyl;
(6) -OC(0)-N(R 24 )(R 2 5) wherein R 24 and R 25 are independently selected
from
(a) hydrogen,
(b) loweraikyl,
(c) alkenyl,
(d) alkynyl,
(e) cycloalkyl,
(f) substituted loweraikyl, substituted alkenyl, substituted alkynyl
or substituted cycloalkyl wherein the loweraikyl group, the
alkenyl group, the alkynyl group or the cycloalkyl group is
substituted by one or two substituents independently selected from
(i) hydroxy,
(ii) -COOH,
PCT/US94/12777
-28-
(iii) -CN,
(iv) -Q-loweralkyl, -Q-aryl, -Q-(arylalkyl), -Q-heterocyclic
or -Q-(heterocyclicalkyl) wherein Q is -O-, -S-, -S(O)-,
-S(0) 2 -, -C(O)-, -OC(O)-, -C(0)0-, -C(0)C(0)-0-,
-0-C(0)C(0)-, -C(0)NH-, -NHC(O)-, -OC(0)NH-,
-NHC(0)0-, -NH-C(0)-NH-, -S(0) 2 NH-, -NHS(0) 2 -,
-N(R 2 7)-, -C(NR27)NHNH- and -NHNHC(NR27)- wherein
R 27 is hydrogen, loweralkyl, aryl or heterocyclic,
(v) cycloalkyl,
(vi) aryl,
(vii) heterocyclic,
(viii) -N(R 2 8)(R29) wherein R 28 and R 2 9 are independently
selected from hydrogen, loweralkyl, hydroxyalkyl, aryl
and heterocyclic,
(ix) guanidino,
(x) -S(0) 2 R 11 wherein R 11 is loweralkyl, aryl or arylalkyl,
(xi) -OS(0) 2 R n wherein R 11 is defined as above,
(xii) -SO3H,
(xiii) -S(0) 2 NH 2 ,
(xiv) -SR 28 wherein R 28 is defined as above,
. (xv) halogen,
(xvi) oxo and
(xvii) epoxy;
(g) aryl,
(h) heterocyclic,
(i) -NHC(0)-0-loweralkyl,
(j) -NHC(0)-aryl,
(k) -NHC(0)-heterocyclic and
(1) loweralkyl substituted by -OC(0)-R f wherein R f is
carboxyalkyl
or -N(R 24 )(R 25 ) taken together form a nitrogen-containing
heterocyclic group,
(7) -OR 25 wherein R 25 is as defined above,
(8) a protected hydroxy group,
-29-
(9) -OC(0)N(OR 24 )(R25) wherein R24 and R 25 are defined as above,
(10) -0(CH 2 )jC(0)OR 20 wherein i is one or two and R 20 is independently
defined as above,
(11) -O(CH(Si(CH3)3))-(CH 2 )jC(O)OR 2 0 wherein j is zero or one and
R 2 ^ is independently defined as above,
(12) -0(CH 2 )jC(0)N(R24)(R25) wherein i, R 24 and R 2 5 are defined as
above,
(13) -0(CH 2 )jC(0)N(OR24)(R25) wherein i, R 24 and R 2 $ are defined as
above,
(14) -0(CH 2 ) i C(0)N(R 24 )(N(R 24 )(R 2 5)) wherein i, R 24 and R25 are
defined as above,
(15) -0(CH 2 )jNHC(0)N(R24)(R25) wherein i, R24 and R 25 are defined as
above,
(16) -0(CH 2 ) i NHC(0)N(OR 24 )(R25) wherein i, R24 and R25 are defined
as above,
(17) -0(CH 2 ) i NHC(0)N(R24)(N(R24)(R25)) wherein i, R24 and R25 are
defined as above,
(18) -OS(0) 2 N(R24)(R25) wherein R24 an d R25 are defined as above,
(19) -0(CH 2 ) r NHC(0)R24 wherein R 2 4 is defined as above,
(20) -OCH(R24)-SH wherein R 2 4 i s defined as above,
(21) -OCH(R24)-S-loweralkyl wherein R24 i s defined as above,
(22) -OCH(R24)-S-aryl wherein R24 i s defined as above,
(23) -N 3 ,
(24) -N=C=0,
(25) -N(R24)(R25) wherein R 24 and R 25 are defined as above,
(26) -NHC(0)-R24 wherein R24 i s defined as above,
(27) -NHC(0)-N(R24)(R25) wherein R 2 4 and R 25 are defined as above,
(28) -S-R24 wherein R24 i s defined as above and
(29) -S-q-R 24 wherein q is a divalent radical selected from the group
consisting of -S-, -C(O)-, -C(0)-0-, -C(0)-NH- and -C(N(R 2 ?))-NHNH-
and R 24 and R 2 ? are defined as above,
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-30-
with the proviso that one of R 8 and R 9 is hydrogen and the other is not
hydrogen and one of R 18 and R 19 is hydrogen and the other is not
hydrogen; or
R 8 and R 9 taken together are
5 (1) oxo,
(2) =N-0-R 24 wherein R 24 is defined as above or
(3) =N-N(R 24 )(R 2 5) wherein R 24 and R 25 are defined as above; or
R 18 and R 19 taken together are
(1) oxo,
10 (2) =N-0-R 24 wherein R 24 is independently defined as above or
(3) =N-N(R 24 )(R 25 ) wherein R 24 and R 25 are independently defined as
above; or
one of R 8 and R 9 taken together with one of R 18 and R 19 form a heterocyclic ring
with the others of R 8 , R 9 , R 18 and R 19 being hydrogen or together forming a
15 bond; or
R 8 and R 18 are hydrogen and R 8 ' and R 19 form a bond;
RlOa j s hydrogen and R 10b is hydrogen, hydroxy, protected hydroxy, alkoxy,
alkenyl, alkenyloxy, halogen or -SR 28 wherein R 28 is independently defined as
20 above or R 10b is hydrogen and R 10a is hydrogen, hydroxy, protected hydroxy,
alkoxy, alkenyl, alkenyloxy, halogen or -SR 28 wherein R 28 is independently
defined as above or R 10a and R 10b are both alkoxy or -SR 28a wherein R 28a is
loweralkyl, aryl or heterocyclic or R 10a and R 10b taken together are oxo; and
25 X is hydrogen and Y is hydrogen, hydroxy or protected hydroxy or Y is hydrogen
and X is hydroxy or protected hydroxy or X and Y taken togehter are oxo;
or a pharmaceutically acceptable salt, ester, amide or prodrug thereof.
30
WO 95/14023
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-31-
Preferred compounds of the formula IV are those wherein:
Zis
5
10 Rl is methyl;
R 2 is hydrogen and R 3 is hydroxy;
R 4 is hydrogen and R5 is hydroxy or R 5 is hydrogen and R 4 is hydroxy or R 4 and
R 5 taken together are oxo;
R 6 and R 7 are defined as above;
15 R!0a i s hydrogen, methoxy or fluoro and R 10b is hydrogen; and
X and Y taken together are oxo.
More preferred compounds of the formula IV are those wherein:
Z is
20
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-32-
(c)
10
15
20
R 1 is methyl;
R 2 is hydrogen and R 3 is hydroxy;
R 4 is hydrogen and R 5 is hydroxy or R 5 is hydrogen and R 4 is hydroxy or R 4 and
R 5 taken together are oxo;
R 6 and R 7 taken together are
(1) oxo,
(2) =N-OR 20 wherein R 20 is hydrogen, loweralkyl, alkenyl, cycloalkyl,
cycloalkenyl, bicycloalkenyl, aryl, arylalkyl, heterocyclic or
heterocyclicalkyl, each of which is optionally substituted with loweralkyl,
halogen, hydroxy, aryl or heterocyclic; or
(3) =N-N(R 21 )(R 22 ) wherein R 21 and R 22 are independently selected
from hydrogen, loweralkyl, aryl, arylalkyl, heterocyclic and
heterocyclicalkyl;
RlOa i s hydrogen, methoxy or fluoro and R 10b is hydrogen; and
X and Y taken together are oxo.
Even more preferred compounds of the formula IV are those wherein:
Zis
(a)
H
WO 95/14023
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-33-
R 1 is methyl;
R 2 is hydrogen and R 3 is hydroxy;
5 R 4 and R^ taken together are oxo;
R 6 and R 7 taken together are
(1) oxo,
(2) =N-OR 20 wherein R 20 is hydrogen, loweraikyl, alkenyl, cycloalkyl,
cycloalkenyl, bicyclo alkenyl, aryl, arylalkyl, heterocyclic or
10 heterocyclicalkyl, each of which is optionally substituted with loweraikyl,
halogen, hydroxy, aryl or heterocyclic; or
(3) =N-N(R 21 )(R 22 ) wherein R 21 and R 22 are independently selected
from hydrogen, loweraikyl, aryl, arylalkyl, heterocyclic and
heterocyclicalkyl;
15
R 10a is methoxy and R 10b is hydrogen; and
X and Y taken together are oxo.
Most preferred compounds of the formula IV are those wherein:
20 Zis
WO 95/14023
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-34-
R 1 is methyl;
R 2 is hydrogen and R 3 is hydroxy;
5 R 4 and R 5 taken together are oxo;
R 6 and R 7 taken together are oxo;
R!0 a is methoxy and R 10b is hydrogen; and
X and Y taken together are oxo.
10
In another aspect of the present invention there are compounds of the
formula V:
wherein R 1 is hydrogen, a hydroxy protecting group, loweralkyl or phenyl-
substituted loweralkyl;
20 R 2 is hydrogen and R 3 is hydroxy or protected hydroxy or R 2 and R 3 taken
together are oxo;
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-35-
R 4 is hydrogen or phenyl- substituted loweralkyl and R 5 is hydroxy or protected
hydroxy or R 5 is hydrogen or phenyl-substituted loweralkyl and R 4 is hydroxy or
protected hydroxy or R 4 and R 5 taken together are oxo;
5 R 6 is hydrogen or phenyl-substituted loweralkyl and R 7 is hydrogen, hydroxy or
protected hydroxy or R 7 is hydrogen or phenyl-substituted loweralkyl and R 6 is
hydroxy or protected hydroxy or R 6 and R 7 taken together are
(1) oxo,
(2) diazo,
10 (3) =CH 2
(4) -0-(CH 2 ) 2 -0-,
(5) -S-(CH 2 ) 2 -S-,
(6) -0-(CH 2 ) 3 -0-,
(7) -S-(CH 2 ) 3 -S-,
15 (8) =N-OR 20 wherein R 20 is hydrogen, loweralkyl, alkenyl, cycloalkyl,
cycloalkenyl, bicycloalkenyl, aryl, arylalkyl, heterocyclic or
heterocyclicalkyl, each of which is optionally substituted with loweralkyl,
halogen, hydroxy, aryl or heterocyclic; or
(9) =N-N(R 21 )(R 22 ) wherein R 21 and R 22 are independendy selected
20 from hydrogen, loweralkyl, aryl, arylalkyl, heterocyclic and
heterocyclicalkyl;
R 8 is
(1) -OC(O)N(OR 20 )(R 24 ) or
25 (2) -0-C(0)-NHN(R 24 )(R 2 5)
wherein R 20 is hydrogen, loweralkyl, alkenyl, cycloalkyl, cycloalkenyl,
bicycloalkenyl, aryl or heterocyclic, each of which is optionally
substituted with loweralkyl, hydroxy, aryl or heterocyclic and R 24 and
R 25
are independendy selected from
30 (a) hydrogen,
(b) loweralkyl,
(c) alkenyl,
(d) alkynyl,
PCT/US94/12777
-36-
(e) cycloalkyl,
(f) substituted loweralkyl, substituted alkenyl, substituted alkynyl
or substituted cycloalkyl wherein the loweralkyl group, the
alkenyl group, the alkynyl group or the cycloalkyl group is
substituted by one or two substituents independently selected from
(i) hydroxy,
(ii) -COOH,
(iii) -CN,
(iv) -Q-loweralkyl, -Q-aryl, -Q-(arylalkyl), -Q-heterocyclic
or -Q-(heterocyclicalkyl) wherein Q is -O-, -S-, -S(O)-,
-S(0) 2 -, -C(O)-, -OC(O)-, -C(0)0-, -C(0)C(0)-0-,
-0-C(0)C(0)-, -C(0)NH-, -NHC(O)-, -OC(0)NH-,
-NHC(0)0-, -NH-C(0)-NH-, -S(0) 2 NH-, -NHS(0) 2 -,
-N(R 2 7)-, -C(NR 2 7)NHNH- and -NHNHC(NR27)- wherein
R 27 is hydrogen, loweralkyl, aryl or heterocyclic,
(v) cycloalkyl,
(vi) aryl,
(vii) heterocyclic,
(viii) -N(R 28 )(R 29 ) wherein R 28 and R 29 are independently
selected from hydrogen, loweralkyl, hydroxyalkyl, aryl
and heterocyclic,
(ix) guanidino,
(x) -S(0) 2 R 11 wherein R 11 is loweralkyl, aryl or arylalkyl,
(xi) -OSCO^R 11 wherein R 11 is defined as above,
(xii) -SO3H,
(xiii) -S(0) 2 NH 2 ,
(xiv) -SR 28 wherein R 28 is defined as above,
(xv) halogen,
(xvi) oxo and
(xvii) epoxy;
(g) aryl,
(h) heterocyclic,
(i) -NHC(0)-0-loweralkyl,
(j) -NHC(0)-aryl,
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-37-
(k) -NHC(0)-heterocyclic or
(1) loweralkyl substituted by -OC(0)-R f wherein R f is
carboxyalkyl
or -N(R 24 )(R 25 ) taken together form a nitrogen-containing
5 heterocyclic group;
R9 is hydrogen;
RlOa j s hydrogen and R 10b is hydrogen, hydroxy, protected hydroxy, alkoxy,
10 alkenyl, alkenyloxy, halogen or -SR 28 wherein R 28 is independently defined as
above or R 10b is hydrogen and R 10a is hydrogen, hydroxy, protected hydroxy,
alkoxy, alkenyl, alkenyloxy, halogen or -SR 28 wherein R 28 is independently
defined as above or R 10a and R 10b are both alkoxy or -SR 28a wherein R 28a is
loweralkyl, aryl or heterocyclic or R 1 ^ and R 10b taken together are oxo; and
15
X is hydrogen and Y is hydrogen, hydroxy or protected hydroxy or Y is hydrogen
and X is hydroxy or protected hydroxy or X and Y taken togehter are oxo;
or a pharmaceutically acceptable salt, ester, amide or prodrug thereof.
20
Preferred compounds of the formula V are those wherein:
R 1 is methyl;
R 2 is hydrogen and R 3 is hydroxy;
R 4 is hydrogen and R 5 is hydroxy or R 5 is hydrogen and R 4 is hydroxy or R 4 and
25 R 5 taken together are oxo;
R 6 and R 7 are defined as above;
R 8 is defined as above;
R9 is hydrogen;
RlOa i s hydrogen, methoxy or fluoro and R 10b is hydrogen;
30 R 20 is defined as above;
R 24 is defined as above; and
X and Y taken together are oxo.
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More preferred compounds of the formula V are those wherein:
R 1 is methyl;
R 2 is hydrogen and R 3 is hydroxy;
R 4 is hydrogen and R 5 is hydroxy or R 5 is hydrogen and R 4 is hydroxy or R 4 and
5 R 5 taken together are oxo;
R 6 and R 7 taken together are
(1) oxo,
(2) =N-OR 20 wherein R 20 is hydrogen, loweralkyl, alkenyl, cycloalkyl,
cycloalkenyl, bicycloalkenyl, aryl, arylalkyl, heterocyclic or
10 heterocyclicalkyl, each of which is optionally substituted with loweralkyl,
halogen, hydroxy, aryl or heterocyclic; or
(3) =N-N(R 21 )(R 22 ) wherein R 21 and R 22 are independently selected
from hydrogen, loweralkyl, aryl, arylalkyl, heterocyclic and
heterocyclicalkyl;
R8 is -OC(O)N(OR 2 0)(R 24 ) wherein R 20 and R 24 are defined as above;
RlOa j s hydrogen, methoxy or fluoro and R 10b is hydrogen; and
X and Y taken together are oxo.
Even more preferred compounds of the formula V are those wherein:
R 1 is methyl;
R 2 is hydrogen and R 3 is hydroxy;
R 4 and R 5 taken together are oxo;
R 6 and R 7 taken together are oxo;
R 8 is -OC(O)N(OR 20 )(R 24 ) wherein R 20 is hydrogen, loweralkyl or arylalkyl and
R 24 is hydrogen, loweralkyl or cycloalkyl;
R 10a is methoxy and R 10b is hydrogen; and
X and Y taken together are oxo.
Most preferred compounds of the formula V are those wherein:
R 1 is methyl;
R 2 is hydrogen and R 3 is hydroxy;
R 4 and R 5 taken together are oxo;
R 6 and R 7 taken together are oxo;
WO 95/14023
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-39-
R 8 is -OC(O)N(OR 20 )(R 24 ) wherein R 20 is hydrogen, methyl or benzyl and R 24 is
hydrogen or methyl;
R 10a is methoxy and R 10b is hydrogen; and
X and Y taken together are oxo.
5
In another aspect of the present invention there are compounds of the
formula VI:
wherein R is F;
15 R 1 is hydrogen, a hydroxy protecting group, loweralkyl or phenyl- substituted
loweralkyl;
R 2 is hydrogen and R 3 is hydroxy or protected hydroxy or R 2 and R 3 taken
together are oxo;
20
R 4 is hydrogen or phenyl-substituted loweralkyl and R 5 is hydroxy or protected
hydroxy or R 5 is hydrogen or phenyl-substituted loweralkyl and R 4 is hydroxy or
protected hydroxy or R 4 and R 5 taken together are oxo;
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R 6 is hydrogen or phenyl-substituted loweralkyl and R 7 is hydrogen, hydroxy or
protected hydroxy or R 7 is hydrogen or phenyl-substituted loweralkyl and R 6 is
hydroxy or protected hydroxy or R 6 and R 7 taken together are
(1) oxo,
(2) diazo,
(3) =CH 2
(4) -0-(CH 2 ) 2 -0-,
(5) -S-(CH 2 ) 2 -S-,
(6) -0-(CH 2 ) 3 -0-,
(7) -S-(CH 2 ) 3 -S-,
(8) =N-OR 20 wherein R 20 is hydrogen, loweralkyl, alkenyl, cycloalkyl,
cycloalkenyl, bicycloalkenyl, aryl, arylalkyl, heterocyclic or
heterocyclicalkyl, each of which is optionally substituted with loweralkyl,
halogen, hydroxy, aryl or heterocyclic; or
(9) =N-N(R 21 )(R 22 ) wherein R 21 and R 22 are independently selected
from hydrogen, loweralkyl, aryl, arylalkyl, heterocyclic and
heterocyclicalkyl;
R 9 is hydrogen;
RlOa j s hydrogen and R 10b is hydrogen, hydroxy," protected hydroxy, alkoxy,
alkenyl, alkenyloxy, halogen or -SR 28 wherein R 28 is independently defined as
above or R 10b is hydrogen and R 10a is hydrogen, hydroxy, protected hydroxy,
alkoxy, alkenyl, alkenyloxy, halogen or -SR 28 wherein R 28 is independently
defined as above or R 10a and R 10b are both alkoxy or -SR 28a wherein R 28a is
loweralkyl, aryl or heterocyclic or R 10a and R 10b taken together are oxo; and
X is hydrogen and Y is hydrogen, hydroxy or protected hydroxy or Y is hydrogen
and X is hydroxy or protected hydroxy or X and Y taken togehter are oxo;
or a pharmaceutically acceptable salt, ester, amide or prodrug thereof.
WO 95/14023
PCT/US94/12777
10
.41-
Preferred compounds of the formula VI are those wherein:
Ris F;
R 1 is methyl;
R 2 is hydrogen and R 3 is hydroxy;
R 4 is hydrogen and R 5 is hydroxy or R 5 is hydrogen and R 4 is hydroxy or R 4 and
R 5 taken together are oxo;
R 6 and R 7 are defined as above;
RlOa i s hydrogen, methoxy or fluoro and R 10b is hydrogen; and
X and Y taken together are oxo.
More preferred compounds of the formula VI are those wherein:
Ris F;
R 1 is methyl;
R 2 is hydrogen and R 3 is hydroxy;
15 R 4 is hydrogen and R 5 is hydroxy or R5 is hydrogen and R 4 is hydroxy or R 4 and
R 5 taken together are oxo;
R 6 and R 7 taken together are
(1) oxo,
(2) =N-OR 20 wherein R 20 is hydrogen, loweralkyl, alkenyl, cycloalkyl,
20 cycloalkenyl, bicycloalkenyl, aryl, arylalkyl, heterocyclic or
heterocyclicalkyl, each of which is optionally substituted with loweralkyl,
halogen, hydroxy, aryl or heterocyclic; or
(3) =N-N(R 21 )(R 22 ) wherein R 21 and R 22 are independently selected
from hydrogen, loweralkyl, aryl, arylalkyl, heterocyclic and
25 heterocyclicalkyl;
RlOa i s hydrogen, methoxy or fluoro and R 10b is hydrogen; and
X and Y taken together are oxo.
Even more preferred compounds of the formula VI are those wherein:
30 R is F;
R 1 is methyl;
R 2 is hydrogen and R 3 is hydroxy;
R 4 and R 5 taken together are oxo;
R 6 and R 7 taken together are
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-42-
(1) 0X0,
(2) =N-OR 20 wherein R 20 is hydrogen, loweralkyl, alkenyl, cycloalkyl,
cycloalkenyl, bicycloalkenyl, aryl, arylalkyl, heterocyclic or
heterocyclicalkyl, each of which is optionally substituted with loweralkyl,
5 halogen, hydroxy, aryl or heterocyclic; or
(3) =N-N(R 21 )(R 22 ) wherein R 21 and R 22 are independently selected
from hydrogen, loweralkyl, aryl, arylalkyl, heterocyclic and
heterocyclicalkyl;
R 10a is methoxy and R 10b is hydrogen; and
10 X and Y taken together are oxo.
Most preferred compounds of the formula VI are those wherein:
Ris F;
R 1 is methyl;
15 R 2 is hydrogen and R 3 is hydroxy;
R 4 and R 5 taken together are oxo;
R 6 and R 7 taken together are oxo;
R 10a is methoxy and R 10b is hydrogen; and
X and Y taken together are oxo.
25
30
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-43-
In another aspect of the present invention there are compounds of the
formula VII:
5 VIT
wherein R 1 is hydrogen, a hydroxy protecting group, loweralkyl or phenyl-
substituted loweralkyl;
R 2 is hydrogen and R 3 is hydroxy or protected hydroxy or R 2 and R 3 taken
10 together are oxo;
R 4 is hydrogen or phenyl-substituted loweralkyl and R 5 is hydroxy or protected
hydroxy or R 5 is hydrogen or phenyl-substituted loweralkyl and R 4 is hydroxy or
protected hydroxy or R 4 and R 5 taken together are oxo;
15
R 6 is hydrogen or phenyl-substituted loweralkyl and R 7 is hydrogen, hydroxy or
protected hydroxy or R 7 is hydrogen or phenyl-substituted loweralkyl and R 6 is
hydroxy or protected hydroxy or R 6 and R 7 taken together are
(1) oxo,
20 (2) diazo,
(3) =CH 2
(4) -0-(CH 2 ) 2 -0-,
(5) -S-(CH 2 ) 2 -S-,
(6) -0-(CH 2 ) 3 -0-,
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-44-
(7) -S-(CH 2 ) 3 -S-,
(8) =N-OR 20 wherein R 20 is hydrogen, loweralkyl, alkenyl, cycloalkyl,
cycloalkenyl, bicycloalkenyl, aryl, arylalkyl, heterocyclic or ,
heterocyclicalkyl, each of which is optionally substituted with loweralkyl,
5 halogen, hydroxy, aryl or heterocyclic; or
(9) =N-N(R 21 )(R 22 ) wherein R 21 and R 22 are independently selected
from hydrogen, loweralkyl, aryl, arylalkyl, heterocyclic and
heterocyclicalkyl;
10 R 8 is
(1) -0(CH 2 )jC(0)OR 20 wherein i is one or two and R 20 is independently
defined as above,
(2) -0(CH 2 )jC(0)N(R 2 4)(R25) wherein i is one or two and R 2 * and R 2 5
are independently selected from
15 (a) hydrogen,
(b) loweralkyl,
(c) alkenyl,
(d) alkynyl,
(e) cycloalkyl,
20 (f) substituted loweralkyl, substituted alkenyl, substituted alkynyl
or substituted cycloalkyl wherein the loweralkyl group, the
alkenyl group, the alkynyl group or the cycloalkyl group is
substituted by one or two substituents independently selected from
(i) hydroxy,
25 (ii) -COOH,
(iii) -CN,
(iv) -Q-loweralkyl, -Q-aryl, -Q-(arylalkyl), -Q-heterocyclic
or -Q-(heterocyclicalkyl) wherein Q is -O-, -S-, -S(O)-,
-S(0) 2 -, -C(O)-, -OC(O)-, -C(0)0-, -C(0)C(0)-0-,
30 -0-C(0)C(0)-, -C(0)NH-, -NHC(O)-, -OC(0)NH-,
-NHC(0)0-, -NH-C(0)-NH-, -S(0) 2 NH-, -NHS(0) 2 -,
-N(R 27 )-, -C(NR 27 ) NHNH- and -NHNHC(NR 27 )- wherein
R 27 is hydrogen, loweralkyl, aryl or heterocyclic,
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(v) cycloalkyl,
(vi) aryl,
(vii) heterocyclic,
(viii) -N(R28)(R29) wherein R28 an d R29 are independently
5 selected from hydrogen, loweralkyl, hydroxyalkyl, aryl
and heterocyclic,
(ix) guanidino,
(x) -S(0) 2 R n wherein RH is loweralkyl, aryl or arylalkyl,
(xi) -OS(0) 2 R n wherein RH is defined as above,
10 (xii) -S0 3 H,
(xiii) -S(0) 2 NH 2 ,
(xiv) -SR28 wherein R28 i s defined as above,
(xv) halogen,
(xvi) oxo and
15 (xvii) epoxy;
(g) aryl,
(h) heterocyclic,
(i) -NHC(0)-0-loweralkyl,
0) -NHC(0)-aryl,
20 (k) -NHC(0)-heterocyclic and
(1) loweralkyl substituted by -OC(0)-Rf wherein Rf is
carboxyalkyl
or -N(R24)(R25) ta k en together form a nitrogen-containing
heterocyclic group,
25 (3) -0(CH 2 ) i C(0)N(OR24)( R 25 ) wherein i, R24 an d R25 are defined as
above,
(4) -0(CH 2 ) i C(0)N(R24)( N( R24 )(R 25 )) wherein i, R24 and R25 are
defined as above,
(5) -0(CH 2 ) i NHC(0)N(R24)( R 25 ) wherein i, R24 and R 25 ^ deflned as
30 above,
(6) -(CH 2 ) i NHC(0)N(OR24)( R 25 ) w h er ein i, R24 an d R25 defined as
above or
(7) -(CH 2 ) i NHC(0)N(R24)( N (R24 )(R 25)) whe rein i. R24 and R25 ^
defined as above;
WO 95/14023
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-46-
R 9 is hydrogen;
RlOa i s hydrogen and R 10b is hydrogen, hydroxy, protected hydroxy, alkoxy,
5 alkenyl, alkenyloxy, halogen or -SR 28 wherein R 28 is independendy defined as
above or R 10b is hydrogen and R 10a is hydrogen, hydroxy, protected hydroxy,
alkoxy, alkenyl, alkenyloxy, halogen or -SR 28 wherein R 28 is independendy
defined as above or R 10a and R 10b are both alkoxy or -SR 28a wherein R 28a is
loweralkyl, aryl or heterocyclic or R 10a and R 10b taken together are oxo; and
10
X is hydrogen and Y is hydrogen, hydroxy or protected hydroxy or Y is hydrogen
and X is hydroxy or protected hydroxy or X and Y taken togehter are oxo;
or a pharmaceutically acceptable salt, ester, amide or prodrug thereof.
15
Preferred compounds of the formula VTI are those wherein:
R 1 is methyl;
R 2 is hydrogen and R 3 is hydroxy;
20 R 4 is hydrogen and R 5 is hydroxy or R 5 is hydrogen and R 4 is hydroxy or R 4 and
R 5 taken together are oxo;
R 6 and R 7 are defined as above;
R 8 is defined as above;
R 9 is hdyrogen;
25 R 10a is hydrogen, methoxy or fluoro and R 10b is hydrogen; and
X and Y taken together are oxo.
More preferred compounds of the formula VII are those wherein:
R 1 is methyl;
30 R 2 is hydrogen and R 3 is hydroxy;
R 4 is hydrogen and R 5 is hydroxy or R 5 is hydrogen and R 4 is hydroxy or R 4 and
R 5 taken together are oxo;
R 6 and R 7 taken together are
(1) oxo,
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-47-
(2) =N-OR 20 wherein R 20 is hydrogen, loweralkyl, alkenyl, cycloalkyl,
cycloalkenyl, bicycloalkenyl, aryl, arylalkyl, heterocyclic or
heterocyclicalkyl, each of which is optionally substituted with loweralkyl,
halogen, hydroxy, aryl or heterocyclic; or
(3) =N-N(R 21 )(R 22 ) wherein R 21 and R 22 are independently selected
from hydrogen, loweralkyl, aryl, arylalkyl, heterocyclic and
heterocyclicalkyl;
R8
is
(1) -0(CH 2 ) i C(0)N(R 24 )(R 2 5) wherein i is one or two and R 24 and R 2 5
10 are independently selected from
(a) hydrogen,
(b) loweralkyl,
(c) alkenyl,
(d) alkynyl,
15 (e) cycloalkyl,
(f) substituted loweralkyl, substituted alkenyl, substituted alkynyl
or substituted cycloalkyl wherein the loweralkyl group, the
alkenyl group, the alkynyl group or the cycloalkyl group is
substituted by one or two substituents independently selected from
20 (i) hydroxy,
(ii) -COOH,
(iii) -CN,
(iv) -Q-loweralkyl, -Q-aryl, -Q-(arylalkyl), -Q-heterocyclic
or -Q-(heterocyclicalkyl) wherein Q is -O-, -S-, -S(O)-,
25 -S(0) 2 -, -C(O)-, -OC(O)-, -C(0)0-, -C(0)C(0)-0-,
-0-C(0)C(0)-, -C(0)NH-, -NHC(O)-, -OC(0)NH-,
-NHC(0)0-, -NH-C(0)-NH-, -S(0) 2 NH-, -NHS(0) 2 -,
-N(R 27 )-, -C(NR 27 )NHNH- and -NHNHC(NR 27 )- wherein
R 27 is hydrogen, loweralkyl, aryl or heterocyclic,
30 (v) cycloalkyl,
(vi) aryl,
(vii) heterocyclic,
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-48-
(viii) -N(R 28 )(R 29 > wherein R 28 and R 29 are independently
selected from hydrogen, loweralkyl, hydroxyalkyl, aryl
and heterocyclic,
(ix) guanidino,
5 (x) -S(0) 2 R 11 wherein R 11 is loweralkyl, aryl or arylalkyl,
(xi) -OS(0) 2 R n wherein R 11 is defined as above,
(xii) -S0 3 H,
(xiii) -S(0) 2 NH 2 ,
(xiv) -SR 28 wherein R 28 is defined as above,
10 (xv) halogen,
(xvi) oxo and
(xvii) epoxy;
(g) aryl,
(h) heterocyclic,
15 (i) -NHC(0)-0-loweralkyl,
(j) -NHC(0)-aryl,
(k) -NHC(0)-heterocyclic and
(1) loweralkyl substituted by -OC(0)-R f wherein R f is
carboxyalkyl
20 or -N(R 24 )(R 25 ) taken together form a nitrogen-containing
heterocyclic group or
(2) -0(CH 2 ) i C(0)N(OR 2 4)(R25 ) wherein i, R24 and R 2 5 are defined as
above,
R 9 is hydrogen;
25 R 10a is hydrogen, methoxy or fluoro and R 10b is hydrogen; and
X and Y taken together are oxo.
Even more preferred compounds of the formula VII are those wherein:
R 1 is methyl;
30 R 2 is hydrogen and R 3 is hydroxy;
R 4 and R 5 taken together are oxo;
R 6 and R 7 taken together are
(1) oxo,
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-49-
(2) =N-OR 20 wherein R 20 is hydrogen, loweralkyl, alkenyl, cycloalkyl,
cycloalkenyl, bicycloalkenyl, aryl, arylalkyl, heterocyclic or
heterocyclicalkyl, each of which is optionally substituted with loweralkyl,
halogen, hydroxy, aryl or heterocyclic; or
5 (3) =N-N(R 21 )(R 22 ) wherein R 21 and R 22 are independently selected
from hydrogen, loweralkyl,- aryl, arylalkyl, heterocyclic and
heterocyclicalkyl;
R8 is -0(CH 2 ) i C(0)N(R 2 4)(R 2 5) wherein i is one or two and R 24 and R25 are
independently selected from
10 (a) hydrogen,
(b) loweralkyl,
(c) alkenyl,
(d) alkynyl,
(e) cycloalkyl,
15 (f) substituted loweralkyl, substituted alkenyl, substituted alkynyl
or substituted cycloalkyl wherein the loweralkyl group, the
alkenyl group, the alkynyl group or the cycloalkyl group is
substituted by one or two substituents independently selected from
(i) hydroxy,
20 (ii) -COOH,
(iii) -CN,
(iv) -Q-loweralkyl, -Q-aryl, -Q-(arylalkyl), -Q-heterocyclic
or -Q-(heterocyclicalkyl) wherein Q is -O-, -S-, -S(O)-,
-S(0) r , -C(O)-, -OC(O)-, -C(0)0-, -C(0)C(0)-0-,
25 -0-C(0)C(0)-, -C(0)NH-, -NHC(O)-, -OC(0)NH-,
-NHC(0)0-, -NH-C(0)-NH-, -S(0) 2 NH-, -NHS(0) 2 -,
-N(R 27 )-, -C(NR 27 )NHNH- and -NHNHC(NR 27 )- wherein
R 27 is hydrogen, loweralkyl, aryl or heterocyclic,
(v) cycloalkyl,
30 (vi) aryl,
(vii) heterocyclic,
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-50-
(viii) -N(R 28 )(R 29 ) wherein R 28 and R 29 are independently
selected from hydrogen, loweralkyl, hydroxyalkyl, aryl
and heterocyclic,
(ix) guanidino,
5 (x) -S(0) 2 R 11 wherein R 11 is loweralkyl, aryl or arylalkyl,
(xi) -OS(0) 2 R 11 wherein R 11 is defined as above,
(xii) -S0 3 H,
(xiii) -S(0) 2 NH 2 ,
(xiv) -SR 28 wherein R 28 is defined as above,
10 (xv) halogen,
(xvi) oxo and
(xvii) epoxy;
(g) aryl,
(h) heterocyclic,
15 (i) -NHC(0)-0-loweralkyl,
(j) -NHC(0)-aryl,
(k) -NHC(0)-heterocyclic and
(1) loweralkyl substituted by -OC(0)-R f wherein R f is
carboxyalkyl
20 or -N(R 24 )(R 25 ) taken together form a nitrogen-containing
heterocyclic group,
R 9 is hydrogen;
R 10a is methoxy and R 10b is hydrogen; and
X and Y taken together are oxo.
25
Even more preferred compounds of the formula VET are those wherein:
R 1 is methyl;
R 2 is hydrogen and R 3 is hydroxy;
R 4 and R 5 taken together are oxo;
30 R 6 and R 7 taken together are
(1) oxo,
(2) =N-OR 2 ^ wherein R 20 is hydrogen, loweralkyl, alkenyl, cycloalkyl,
cycloalkenyl, bicycloalkenyl, aryl, arylalkyl, heterocyclic or
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heterocyclicalkyl, each of which is optionally substituted with loweralkyl,
halogen, hydroxy, aryl or heterocyclic; or
(3) =N-N(R2l)(R22) wherein R21 and R22 are independently selected
from hydrogen, loweralkyl, aryl, arylalkyl, heterocyclic and
5 heterocyclicalkyl;
R8 is -0(CH 2 ) i C(0)N(OR24)(R25) wherein £ is one QJ . tWQ and r24 and r25 ^
independently selected from
(a) hydrogen,
(b) loweralkyl,
!0 (c) alkenyl,
(d) alkynyl,
(e) cycloalkyl,
(f) substituted loweralkyl, substituted alkenyl, substituted alkynyl
or substituted cycloalkyl wherein the loweralkyl group, the
15 alkenyl group, the alkynyl group or the cycloalkyl group is
substituted by one or two substituents independently selected from
(i) hydroxy,
(ii) -COOH,
(iii) -CN,
20 < iv > "Q-loweralkyl, -Q-aryl, -Q-(arylalkyl), -Q-heterocyclic
or -Q-(heterocyclicalkyl) wherein Q is -O-, -S-, -S(O)-,
-S(0) 2 -, -C(O)-, -OC(O)-, -C(0)0-, -C(0)C(0)-0-,
-0-C(0)C(0)-, -C(0)NH-, -NHC(O)-, -OC(0)NH-
-NHC(0)0-, -NH-C(0)-NH-, -S(0) 2 NH-, -NHS(0) 2 -,
25 -N(R27)., -C(NR27 )N HNH- and -NHNHC(NR27). wherein
R 27 is hydrogen, loweralkyl, aryl or heterocyclic,
(v) cycloalkyl,
(vi) aryl,
(vii) heterocyclic,
30 < viii > -N(R 2 8)(R29) wherein R28 and R 29 are independently
selected from hydrogen, loweralkyl, hydroxyalkyl, aryl
and heterocyclic,
(ix) guanidino,
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-52-
(x) -S(0) 2 R 11 wherein R 11 is loweralkyl, aryl or arylalkyl,
(xi) -OS(0) 2 R 11 wherein R 11 is defined as above,
(xii) -SO3H,
(xiii) -S(0) 2 NH 2 ,
5 (xiv) -SR 28 wherein R 28 is defined as above,
(xv) halogen,
(xvi) oxo and
(xvii) epoxy;
(g) aryl,
10 (h) heterocyclic,
(i) -NHC(0)-0-loweralkyl,
G) -NHC(0)-aryl,
(k) -NHC(0)-heterocyclic and
(1) loweralkyl substituted by -OC(0)-R f wherein R f is
15 carboxyalkyl
or -N(R 24 )(R 25 ) taken together form a nitrogen-containing
heterocyclic group,
R9 is hydrogen;
R 10a is methoxy and R 10b is hydrogen; and
20 X and Y taken together are oxo.
Most preferred compounds of the formula VII are those wherein:
R 1 is methyl;
R 2 is hydrogen and R 3 is hydroxy;
25 R 4 and R 5 taken together are oxo;
R 6 and R 7 taken together are oxo;
R 8 is -0(CH 2 )iC(0)N(OR 24 )(R 25 ) wherein i is one or two and R 24 is hydrogen,
loweralkyl or arylalkyl and R 25 is hydrogen, loweralkyl or cycloalkyl;
R 9 is hydrogen;
30 R 10a is methoxy and R 10b is hydrogen; and
X and Y taken together are oxo.
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When examined for immunomodulatory activity using a common in vitro
biological assay, the compounds of the invention are seen to be potent
immunosuppressive agents. The compounds of this invention possess
5 immunosuppressive, antimicrobial, antifungal, antiviral, antiinflammatory and
antiproliferative activity. Moreover, the compounds of the invention possess the
ability to reverse chemotherapeutic drug resistance. As agents which block T-
cell activation, a prerequisite for HIV proliferation, the compounds are useful as
prophylactics for the prevention of HIV replication. While, the compounds of
10 the invention are useful when used independently of other agents, combination
therapy with other immunosuppressants is beneficial as well. These other
immunosuppressant agents include but are not limited to FK-506, rapamycin,
cyclosporin A, mycophenolic acid, azathioprine, prednisolone,
cyclophosphamide, brequinar and leflunomide.
15 Accordingly, in another aspect of the present invention are disclosed
pharmaceutical compositions comprising a compound of the present invention in
combination with a pharmaceutically acceptable carrier. Suitable carriers and
methods of formulation are also disclosed.
In a further aspect of the present invention are disclosed processes for the
20 preparation of the above compounds, synthetic intermediates useful in the
preparations of these and other immunomodulatory derivatives of rapamycin.
In yet another aspect of the present invention is disclosed a method of
immunomodulatory treatment in a human or lower mammal, comprising
administering to the patient a therapeutically effective amount of at least one
25 compound of this invention.
Throughout this specification and in the appended claims, the following
terms have the meanings specified:
The term "alkanoylamino" as used herein refers to -NHC(0)R 108 wherein
30 R^ 8 i s a loweralkyl group.
The term "alkenyl" as used herein refers to a straight or branched chain
radical of 2 to 10 carbon atoms containing at least one carbon-carbon double
bond including, but not limited to, ethenyl, 1-propenyl, 2-propenyl, 2-methyl-l-
propenyl, 1-butenyl, 2-butenyl and the like.
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The term "alkenyloxy" as used herein refers to -OR 100 wherein R 100 is an
alkenyl group, including but not limited to, 2-propenyl-oxy and the like.
The term "alkoxy" as used herein refers to -OR 101 wherein R 101 is a
loweralkyl group including, but not limited to, methoxy, ethoxy, isopropoxy, n-
5 butoxy, sec-butoxy, tert-butoxy and the like.
Theterm "alkoxyalkoxy" as used herein refers to -OR 102 OR 103 wherein
R103 i s a loweralkyl group and R 102 is an alkylene group including, but not
limited to, methoxymethoxy, ethoxymethoxy and the like.
The term "alkoxyalkyl" as used herein refers to an alkyl radical to which
10 is appended an alkoxy group.
The term "alkoxycarbonyl" as used herein refers to -C(0)OR 1 ^ 4 wherein
R 104 is a loweralkyl group including, but not limited to, methoxycarbonyl,
ethoxycarbonyl and the like.
The term "alkoxycarbonylalkenyl" as used herein refers to an alkenyl
15 radical to which is appended an alkoxycarbonyl group.
The term "alkoxycarbonylthioalkoxy" as used herein refers to
-S-R 105 -R 106 wherein R 105 is an alkylene group and R 106 is an alkoxycarbonyl
group.
The term "alkylene" as used herein refers to a divalent group derived
20 from a straight or branched chain saturated hydrocarbon having from 1 to 10
carbon atoms by the removal of two hydrogen atoms, for example methylene,
1,2-ethylene, 1,1-ethylene, 1,3-propylene, 2,2-propylene, and the like.
The term "alkylamino" as used herein refers to -NHR 107 wherein R 107 is
a loweralkyl group.
25 The term "alkylsulfonylamino" as used herein refers to -NHS(0) 2 R 110
wherein R 11 *) is a loweralkyl group.
The term "alkynyl" as used herein refers to a straight or branched chain
radical of 2 to 10 carbon atoms containing at least one carbon-carbon triple bond
including, but not limited to, ethynyl, 1-propynyl, 2-propynyl, 1-butynyl,
30 2-butynyl and the like.
The term "aminocarbonyl" as used herein refers to -C(0)NH 2 -
The term "aminocarbonylalkoxy" as used herein refers to
-O-R 109 -C(O)NH 2 wherein Rl09 is an alkylene group.
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The term "aryl" as used herein refers to a mono-, bi- or tricyclic
carbocyclic ring system having one or two aromatic rings including, but not
limited to, phenyl, naphthyl, tetrahydronaphthyl, indanyl, indenyl, fluorenyl and
the like. Aryl groups can be unsubstituted or substituted with one, two or three
5 substituents independently selected from loweralkyl, halo, haloalkyl, haloalkoxy,
alkenyloxy, alkoxy, alkoxyalkoxy, alkoxycarbonyl, alkoxycarbonylalkenyl,
(alkoxycarbonyl)thioalkoxy, thioalkoxy, amino, alkylamino, dialkylamino,
aminocarbonyl, aminocarbonylalkoxy, alkanoylamino, arylalkoxy, aryloxy,
mercapto, nitro, carboxaldehyde, carboxy, carboxyalkenyl, carboxyalkoxy
10 alkylsulfonylamino, cyanoalkoxy, (heterocyclic)alkoxy, hydroxy,
hydroxyalkoxy, phenyl, phenyl-substituted alkenyl, phenyl-substituted alkynyl,
heterocyclic, -S(0) 2 NH 2 and tetrazolylalkoxy. In addition, substituted aryl
groups include tetrafluorophenyl and pentafluorophenyl.
The term "arylalkoxy" as used herein refers to -OR 113 wherein R 113 is an
15 arylalkyl group.
The term "arylalkyl" as used herein refers to an alkyl radical to which is
appended an aryl group. Examples of arylalkyl include benzyl, 2-phenethyl and
the like.
The term "aryloxy" as used herein refers to -OR 114 wherein R 114 is an
20 aryl group.
The term "bicycloalkenyl" as used herein refers to a bicyclic carbocycle
radical containing at least one double bond. Examples of bicycloalkenyl include
l,2-dihydronaphth-4-yl, 1, 2,3,4- tetrahydronaphth-l-yl, and the like.
The term "carboxyalkenyl" as used herein refers to an alkenyl radical to
25 which is appended a carboxy group.
The term "carboxyalkoxy" as used herein refers to -OR 111 wherein R 111
is a carboxyalkyl group.
The term "carboxyalkyl" as used herein refers to an alkyl radical to which
is appended a carboxy (-C(O)OH) group. Examples of carboxyalkyl include
30 carboxymethyl, 2-carboxyethyl and the like.
The term "cyanoalkoxy" as used herein refers to -0-R 112 -CN wherein
R 112 is a alkylene group.
-56-
The term "cycloalkenyl" as used herein refers to a cycloalkyl group
containing at least one double bond. Examples of cycloalkenyl include
1-cyclohexenyl, cyclohex-l-en-3-yl and the like.
The term "cycloalkyl" as used herein refers to a cyclic radical of 3 to 10
carbons including, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl,
cyclohexyl and the like.
The term "cycloalkylalkyl" as used herein refers to an alkyl radical to
which is appended a cycloalkyl group. Examples of cycloalkylalkyl include
cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl and the like.
The term "dialkylamino" as used herein refers to -NR 115 R 116 wherein
R 115 and R 116 are independently selected from loweralkyl.
The term "diazo" as used herein refers to -N=N-.
The term "epoxy" as used herein refers to
The term "halogen" or "halo" as used herein refers to -CI, -Br, -F or -I.
The term "haloalkoxy" as used herein refers to -OR 117 wherein R 117 is a
haloalkyl group.
The term "haloalkyl" as used herein refers to a loweralkyl radical bearing
at least one halogen substituent, for example, chloromethyl, fluoroethyl or
trifluoromethyl and the like.
The term "heterocyclic ring" or "heterocyclic" or "heterocycle" as used
herein refers to any 3- or 4-membered ring containing a heteroatom selected
from oxygen, nitrogen and sulfur; or a 5-, 6- or 7-membered ring containing one,
two or three nitrogen atoms; one oxygen atom; one sulfur atom; one nitrogen and
one sulfur atom; one nitrogen and one oxygen atom; two oxygen atoms in non-
adjacent positions; one oxygen and one sulfur atom in non-adjacent positions; or
two sulfur atoms in non-adjacent positions. The 5-membered ring has 0-2
double bonds and the 6- and 7-membered rings have 0-3 double bonds. The
The term "guanidino" as used herein refers to
NH
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nitrogen heteroatoms can be optionally quaternized. The term "heterocyclic"
also includes bicyclic groups in which any of the above heterocyclic rings is
fused to a benzene ring or a cyclohexane ring or another heterocyclic ring (for
example, indolyl, quinolyl, isoquinolyl, tetrahydroquinolyl, benzofuryl,
5 dihydrobenzofuryl or benzothienyl and the like). Heterocyclics include:
azetidinyl, oxetanyl, pyrrolyl, pyrrolinyl, pyrrolidinyl, pyrazolyl, pyrazolinyl,
pyrazolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyridyl, piperidinyl,
homopiperidinyl, pyrazinyl, piperazinyl, pyrimidinyl, pyridazinyl, oxazolyl,
oxazolidinyl, isoxazolyl, isoxazolidinyl, morpholinyl, thiomorpholinyl, thiazolyl,
10 thiazolidinyl, isothiazolyl, isothiazolidinyl, indolyl, quinolinyl, isoquinolinyl,
benzimidazolyl, benzothiazolyl, benzoxazolyl, furyl, thienyl, thiazolidinyl,
isothiazolyl, triazolyl, tetrazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, pyrrolyl,
pyrimidyl and benzothienyl. Heterocyclics also include compounds of the
15 [-C(R")2-] V where R" is hydrogen or Ci-C4-alkyl and v is 1, 2 or 3 such as 1,3-
benzodioxolyl, 1,4-benzodioxanyl and the like.
Heterocyclics also include bicyclic spirocyclic heterocycles such as the
ethylene ketal of pyridin-2-on-l-yl, the ethylene ketal of pyridin-4-on-l-yl and
the like.
20 Heterocyclics also include hexose monosaccharides (for example, D-
allose, D-alrrose, D-glucose, D-mannose, D-gulose, D-idose, D-galactose, D-
talose and the like) and pentose monosaccharides (for example, D-ribose, D-
arabinose, D-xylose, D-lyxose and the like).
Heterocyclics can be unsubstituted or mono substituted or disubstituted
25 with substituents independently selected from hydroxy, halo, oxo (=0), amino,
alkylamino, dialkylamino, alkoxy, alkoxyalkoxy, alkoxyalkyl, haloalkyl,
hydroxy, hydroxyalkyl, cycloalkyl, aryl, arylalkyl, -COOH, -SO3H, -C(0)NH 2
and loweralkyl. In addition, nitrogen containing heterocycles can be N-
protected.
30 The term "(heterocyclic)alkyl" as used herein refers to a heterocyclic
group as defined above appended to a loweralkyl radical as defined above.
formula
where X* is -CH2- or -O- and Y* is -C(O)- or
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The term "heterocyclicalkoxy" as used herein refers to -OR 1 18 wherein
Rll8 is a heterocyclicalkyl group.
The term "hydroxyalkyl" as used herein refers to an alkyl radical to
which is appended an hydroxy group. Examples of hydroxyalkyl include
5 hydroxymethyl, 2-hydroxyethyl, 2-hydroxypropyl and the like.
The term "hydroxyalkoxy" as used herein refers to -0-R 119 -OH wherein
R 1 19 is an alkylene group.
The term "hydroxy protecting group" as used herein refers to those
radicals which are known in the art of organic synthesis to protect a hydroxyl
10 group against undesirable reaction during synthetic procedures and to be
selectively removable such as those hydroxy protecting groups disclosed in T.W.
Greene and P.G.M. Wuts, Protective Groups in Organic Synthesis, 2nd ed., John
Wiley & Son, Inc., 1991, which is hereby incorporated herein by reference.
Examples include, but are not limited to, substituted methyl ethers, for example,
15 methoxymethyl, methylthiomethyl, 2-methoxyethoxymethyl, benzyloxymethyl,
2-(trimethylsilyl)ethoxymethyl, t-butyl, benzyl and triphenylmethyl;
tetrahydropyranyl ethers; substituted ethyl ethers, for example, 2,2,2-
trichoroethyl; silyl ethers, for example, dimethylthexylsilyl, trisubstituted silyl
such as tris(loweralkyl)silyl (e.g., trimethylsilyl, triethylsilyl, tributylsilyl, tri-
20 isopropylsilyl, tert-butyldimethyl silyl, tri-rert-butylsilyl, triphenylsilyl,
triphenylmethyldimethylsilyl, etc.), loweralkyldiarylsilyl (e.g.,
methyldiphenylsilyl, ethyldiphenylsilyl, propyldiphenylsilyl, tert-
butyldiphenylsilyl, etc.), triarylsilyl (e.g., triphenylsilyl, trixylylsilyl, etc.) and
triarylalkyl silyl (e.g., tribenzylsilyl, etc.); -C(0)H; -C(0)-loweralkyl (for
25 example, acetyl, propionyl, pivaloyl, t-butylacetyl and the like); -C(0)-aryl (for
example, benzoyl and the like); alkoxycarbonyl (for example, ethoxycarbonyl
and the like); -S(0)2-(loweralkyl); -S(0)2-(aryl); and the like.
The term "loweralkyl" as used herein refers to a monovalent straight
chain or branched chain radical of 1 to 10 carbon atoms including, but not
30 limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-
butyl, decyl and the like.
The term "oxo" as used herein refers to (=0).
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The term "tetrazolylalkoxy" as used herein refers to -O-R 120 -tetrazolyl
wherein R 120 is an alkylene group.
The term "pharmaceutically acceptable salts, esters, amides and
prodrugs" as used herein refers to those carboxylate salts, amino acid addition
5 salts, esters, amides and prodrugs of the compounds of the present invention
which are, within the scope of sound medical judgement, suitable for use in
contact with with the tissues of humans and lower animals with undue toxicity,
irritation, allergic response and the like, commensurate with a reasonable
benefit/risk ratio, and effective for their intended use, as well as the zwitterionic
10 forms, where possible, of the compounds of the invention. The term "salts"
refers to the relatively non-toxic, inorganic and organic acid addition salts of
compounds of the present invention. These salts can be prepared in situ during
the final isolation and purification of the compounds or by separately reacting the
purified compound in its free base form with a suitable organic or inorganic acid
15 and isolating the salt thus formed. Representative salts include the
hydrobromide, hydrochloride, sulfate, bisulfate, phosphate, nitrate, acetate,
oxalate, valerate, oleate, palmitate, stearate, laurate, borate, benzoate, lactate,
phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, naphthylate,
mesylate, glucoheptonate, lactiobionate and laurylsulphonate salts and the like.
20 These may include cations based on the alkali and alkaline earth metals, such as
sodium, lithium, potassium, calcium, magnesium and the like, as well as
nontoxic ammonium, quaternary ammonium and amine cations including, but
not limited to, ammonium, tetramethylammonium, tetraethylammonium,
methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine and the
25 like. (See, for example S. M. Berge et aL, "Pharmaceutical Salts," L Pharm. Sci. .
66: 1-19 (1977) which is incorporated herein by reference.)
Examples of pharmaceutically acceptable, non-toxic esters of the
compounds of this invention include Q-Q alkyl esters wherein the alkyl group
is a straight or branched chain. Acceptable esters also include C5-C7 cycloalkyl
30 esters as well as arylalkyl esters such as, but not limited to benzyl. C1-C4 alkyl
esters are preferred. Esters of the compounds of the present invention may be
prepared according to conventional methods.
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Examples of pharmaceutically acceptable, non-toxic amides of the
compounds of this invention include amides derived from ammonia, primary Cl-
C6 alkyl amines and secondary C1-C6 dialkyl amines wherein the alkyl groups
are straight or branched chain. In the case of secondary amines the amine may
5 also be in the form of a 5 or 6 membered heterocycle containing one secondary
nitrogen atom. Amides derived from ammonia, C1-C3 alkyl primary amides and
di(Cl-C2 alkyl) secondary amides are preferred. Amides of the compounds of
me invention may be prepared according to conventional methods.
The term "prodrug" refers to compounds that are rapidly transformed in
10 vivo to yield the parent compound of the above formula, for example by
hydrolysis in blood. A thorough discussion is provided in T. Higuchi and V.
Stella, "Pro-drugs as Novel Delivery Systems", Vol 14 of the A.C.S. Symposium
Series, and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche,
American Pharmaceutical Association and Pergamon Press, 1987, both of which
15 are incorporated herein by reference.
Where appropriate, prodrugs of derivatives of compounds of the present
invention may be prepared by any suitable method. For those compounds in
which the prodrug moiety is an amino acid or peptide functionality, the
condensation of the amino group with amino acids and peptides may be effected
20 in accordance with conventional condensation methods such as the azide
method, the mixed acid anhydride method, the DCC (dicyclohexylcarbodiimide)
method, the active ester method (p-nitrophenyl ester method, N-hydroxysuccinic
acid imide ester method, cyanomethyl ester method and the like), the Woodward
reagent K method, the DCC-HOBT (1-hydroxy-benzotriazole) method and the
25 like. Classical methods for amino acid condensation reactions are described in
"Peptide Synthesis" Second Edition, M. Bodansky, Y.S. Klausner and M.A.
Ondetti (1976).
As in conventional peptide synthesis, branched chain amino and carboxyl
groups at alpha and omega positions in amino acids may be protected and
30 deprotected if necessary. The protecting groups for amino groups which can be
used involve, for example, benzyloxycarbonyl (Cbz),
o-chlorobenzyloxycarbonyl ((2-Cl)Cbz)), p-nitrobenzyloxycarbonyl (Cbz(NC>2)),
p-methoxybenzyloxycarbonyl(Cbz(OMe)), t-amyloxycarbonyl (Aoc),
isobornealoxycarbonyl, adamantyloxycarbonyl (Adoc), 2-(4-biphenyl)-2-
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propyloxy carbonyl (Bpoc), 9-fluorenyl-methoxycarbonyl (Fmoc),
methylsulfonylethoxy carbonyl (Msc), trifluoroacetyl, phthalyl, formyl, 2-
nitrophenylsulfonyl (Nps), diphenylphosphinothioyl (Ppt) and
dimethylphosphino-thioyl (Mpt).
5 Examples of protecting groups for carboxyl groups include, for example,
benzyl ester (OBzl), cyclohexyl ester, 4-nitrobenzyl ester (OBzlN02), t-butyl
ester (OtBu), 4-pyridylmethyl ester (OPic) and the like.
In the course of the synthesis of certain of the compounds of the present
invention, specific amino acids having functional groups other than amino and
10 carboxyl groups in the branched chain such as arginine, cysteine, serine and the
like may be protected, if necessary, with suitable protecting groups. It is
preferable that, for example, the guanidino group (NG) in arginine may be
protected with nitro, p-toluenesulfonyl (Tos), benzyloxycarbonyl (Z),
adamantyloxycarbonyl (Adoc), p-methoxybenzenesulfonyl, 4-methoxy-2,6-
15 dimethyl-benzenesulfonyl (Mts) and the like; the thiol group in cysteine may be
protected with benzyl, p-methoxybenzyl, triphenylmethyl, acetamidomethyl,
ethylcarbamyl, 4-methylbenzyl (4-MeBzl), 2,4,6-trimethylbenzyl (Tmb) and the
like; and the hydroxy group in serine may be protected with benzyl (Bzl), t-butyl,
acetyl, tetrahydropyranyl (THP) and the like.
20 The term "protected hydroxy" as used herein refers to the oxygen atom of
a hydroxy radical to which has been appended a "hydroxy protecting group"as
defined above.
The compounds of the invention may be prepared using one or more of
25 the processes which follow. The starting materials for use in these processes are
preferably one of the macrolides isolated from culture media obtained in
accordance with known methods by fermentation of Streptomyces
hydroscopicus, which are disclosed in U.S. Patent Nos. 3,929, 992 and 3,993,
749; Journal of Antibiotics 1975, 28 (10), 721-726, 727-732 and Journal of
30 Antibiotics 1978, 31 (6), 539-545. One or more of the processes discussed below
may be then employed to produce the desired compound of the invention.
Such processes comprise:
(a) producing by selective activation a compound of formula I or VI
comprising reacting a corresponding precursor in which one of R 8 and R 9 is
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hydrogen and the other is hydroxy with an appropriate amount of fluorosulfonyl
anhydride under conditions suitable for the production of the desired product;
(b) producing by selective activation a compound of formula I or VI
comprising reacting a corresponding precursor in which one of R 8 and R 9 is
5 hydrogen and the other is hydroxy with an appropriate amount of
trifluomethanesulfonyl anhydride under conditions suitable for the production of
the desired product;
(c) producing a compound of formula I in wherein R 8 is hydrogen
and R 9 is -OC(=0)-0-aryl, -OC(=0)-0-(N-succinimidyl), -OC(=0)-triazole,
10 -OC(=0)-imidazolyl, or -OC(=0)-0-benzotriazolyl by reacting a corresponding
precursor in which R 8 is hydrogen and R 9 is hydroxy with appropriate
chloroformates or activated carbonyl compounds;
(d) producing a compound of formula I wherein R 8 is hydrogen and
and R 9 is -OC(=0)-NR 24 R 25 by reacting a corresponding precursor in which R 8
15 is hydrogen and R 9 is -OC(=0)-0-aryl, -OC(=0)-0-(N-succinimidyl), -OC(=0)-
triazolyl, -OC(=0)-imidazolyl, or -OC(=0)-(hydroxybenzotriazolyl) with
appropriate amines (HNR^R 25 );
(e) producing a compound of formula I in which R 8 is hydrogen and
R 9 is hydroxy by reacting a corresponding precursor in which R 9 is hydrogen
20 and R 8 is -OS(0)2F or -0-S(0)2CF3 with water in an appropriate solvent;
(f) producing a compound of formula I in which R 8 is hydrogen and
R 9 is -O-formyl by reacting a corresponding precursor in which R 9 is hydrogen
and R 8 is -OS(0)2F or -OS(0)2CF3 with N,N-dimethylformamide and water;
(g) producing a compound of formula II or in in which R 8 is
25 hydrogen and R 9 is -SR 24 or -NR 24 R 2 5 by reacting a corresponding precursor in
which R 9 is hydrogen and R 8 is -OS(0) 2 F or -OS(0) 2 CF 3 with H-SR 24 ,
H 2 NC(S)NH 2 , or H-NR 24 R 2 5;
(h) producing a compound of formula I or VII in which one of R 8 and R 9
is hydrogen and the other is -OCH 2 C(0)OR 20 , where R 20 is as defined above, by
30 etherification of the corresponding hydroxy compound;
(i) producing a compound of formula I or VII in which one of R 8 and R 9
is hydrogen and the other is -OCH 2 C(0)NR 24 R 2 5, where NR 24 R 2 5 is as defined
above, by etherification of the corresponding hydroxy compound;
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(j) producing a compound of formula I or VII in which one of R 8 and R 9
is hydrogen and the other is -OCH2C(0)N(OR 24 )R 25 , where R 24 and R 25 are as
defined above, by etherification of the corresponding hydroxy compound;
(k) producing a compound of formula I or VII in which one of R 8 and R 9
5 is hydrogen and the other is -OCH2C(0)NR 24 NR 24 R 25 , where R 24 and R 25 are
as defined above, by etherification of the corresponding hydroxy compound;
(1) producing a compound of formula I or VII in which one of R 8 and R 9
is hydrogen and the other is -OCH2-NHC(0)R 24 , where R 24 is as defined above,
by etherification of the corresponding hydroxy compound;
10 (m) producing a compound of formula I or VII in which one of R 8 and R 9
is hydrogen and the other is -OCH2-NHC(0)NR 24 R 25 , wherein -NR 24 R 25 is as
defined above, by etherification of the corresponding hydroxy compound;
(n) producing a compound of formula I or VII in which one of R 8 and R 9
is hydrogen and the other is -OCH2-NHC(0)N(OR 24 )(R 2 5), wherein -NR^R 25
15 is as defined above, by etherification of the corresponding hydroxy compound;
(o) producing a compound of formula I or VII in which one of R 8 and R 9
is hydrogen and the other is -OCH2-NHC(0)NR 24 NR 24 R 2 5, wherein -NR 24 R 25
is as defined above, by etherification of the corresponding hydroxy compound;
(p) producing a compound of formula I or VII in which one of R 8 and R 9
20 is -OCH2-NHC(0)R 24 and the other is hydrogen by (i) activating a
corresponding -OCH2C(0)OH functionality, (ii) generating therefrom, directly
or in a subsequent synthetic step, a -OCH2C(0)N3 functionality, (iii) performing
a Curtius rearrangement, (iv) trapping with a carboxylic acid having the formula
R 24 C0 2 H, and (v) heating to generate the desired -OCH 2 -NHC(0)R 24 moiety;
25 and
(q) producing a compound of formula I or VII in which one of R 8 and R 9
is hydrogen and the other is -OCH2-NHC(0)NR 24 R 2 5, wherein -NR 24 R 25 is as
defined above, by formation of a -OCH2-N=C=0 isocyanate group followed by
addition of an amine HNR 14 R 15 ;
30 (r) producing a compound of formula I or VII in which one of R 8 and R 9
is hydrogen and the other is -OCH 2 C(0)NR 24 R 2 5, where R 24 and R 25 are as
defined above, by condensation of NHR 24 R 25 with a -OCH2C(0)OR 20 group in
a corresponding compound;
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(s) producing a compound of formula I or VII in which one of R 8 and R 9
is hydrogen and the other is -OCH 2 C(0)N(OR 24 )R 25 , where R 24 and R 25 are as
defined above, by condensation of NH(OR 24 )R 25 with a -OCH 2 C(0)OR 20 group
in a corresponding compound;
5 (t) producing a compound of formula I or VII in which one of R 8 and R 9
is hydrogen and the other is -OCH2C(0)NR 24 NR 24 R 25 , where R 24 and R 25 are
as defined above, by condensation of NHR^NR^R 25 with a -OCH 2 C(0)OR 20
group in a corresponding compound;
(u) producing a compound of formula I or VII in which one of R 8 and R 9
10 is hydrogen and the other is -OCH 2 -NHC(0)N(OR 24 )R 25 , wherein R 24 and R 25
are as defined above, by formation of a -OCH 2 -N=C=0 isocyanate group
followed by addition of HN(OR 24 )R 25 ;
(v) producing a compound of formula I or VQ in which one of R 8 and R 9
is hydrogen and the other is -OCH 2 -NHC(0)NR 24 NR 24 R 25 , wherein -NR 24 R 25
15 and R 24 are as defined above, by formation of a -OCH 2 -N=C=0 isocyanate
group followed by addition of HNR^NR^R 25 ;
(w) producing a compound of formula I, wherein R 9 is -N3, by
displacement of an -OS(0) 2 F or -OS(0) 2 CF3 group in a corresponding
compound;
20 (x) . producing a compound of formula III, wherein R 9 is -NH 2 , by
reduction of the -N3 group in a corresponding compound;
(y) producing a compound of formula III, wherein R 9 is -NHCOR*, by
acylation of the corresponding amine;
(z) producing a compound of formula HI, wherein R 9 is
25 -NHC(0)NR a R b , by acylation of the corresponding amine;
(aa) producing a compound of formula IE, wherein R 9 is a -NH-S0 2 R*
group, by selective sulfonylation of the corresponding amine;
(bb) producing a compound of formula III, wherein R 9 is -NH-C(=0)OR
group, by acylation of the corresponding amine;
30 (cc) producing a compound of formula in, wherein R 9 is -NH-SR*, by
sulfenylation of the corresponding amine;
(dd) producing a compound of formula III, wherein R 9 is- -N=C=0, by
isocynate formation from the corresponding amine;
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(ee) producing a compound of formula HI, wherein R 9 is -Se-Ph, by
displacement of a corresponding -OS(0)2F or -OS(0)2CF3 group;
(ff) producing a compound of formula n, wherein R 9 is -Se(0)-Ph, by
oxidation of a corresponding -SePh group;
5 (gg) producing a compound of formula IV, where one of R 8 and R 9 with
one of R 18 and R 19 taken together form a bond, the others of R 8 , R 9 , R 18 and
R 19
are hydrogen, by selective 1,2-eliminaion of an H-OSePh group in a
corresponding compound containing an -Se(0)Ph group;
(hh) producing a compound of formula IV, where one of R 8 and R 9 is
10 OH and one of R 18 and R 19 is OH, and the others of R 8 , R 9 , R 18 and R 19 are
hydrogen by selective 1,2-dihydroxylation of an olefin of a corresponding
compound;
(ii) producing a compound of formula IV, where R 8 or R 9 and R 18 or
R 19 taken together form a -OC(=0)0-, -OS(=0)0-, -OS(0)2-, -0(CH2)0- or
15 -CO(CH2) m CO-, where m=0 to 6, and the others of R 8 , R 9 , RlS and R 19 are
hydrogen by selective functionalization of a 1,2-dihydroxy group of a
corresponding compound;
(jj) producing a compound of formula I- VII, where R 10a = R 10b = H
from a corresponding compound;
20 (kk) producing a compound of formula I- VII, where R 10a = H, R 10b =
OCH3, or R 10a = allyl, R 10b = H from a corresponding compound;
(11) producing a compound of formula IVc where R 8 and R 9 taken
together are oxo, by reacting a compound of formula I wherein R 8 is hydrogen
and R 9 is -OH or R 8 is OH and R 9 is hydrogen with fluorosulfonyl anhydride or
25 trifluoromethylsulfonyl anhydride, followed by reaction of the resulting
sulfonate with silica gel or an appropriate base to produce the enol ether,
followed by hydrolysis of the enol ether; or
(mm) producing a compound of formula IVd by rearrangement of a
compound of formula I where R 8 is -OS0 2 F or -OS0 2 CF 3 and R 9 is hydrogen,
30 in the presence of silica gel or appropriate mild acid under conditions suitable for
the production of the desired product and hydrolysis of the enol ether.
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In process (a), a suitable reagent for activation of an alcohol is
fluorosulfonyl anhydride (prepared according to the procedure described by S.
Kongpricha, W.G. Preusse and R. Schwarer, in Inorganic Synthesis, 1968, 11,
pp. 15 1-155). The activation may be carried out in a solvent which does not
5 adversely affect the reaction (e.g. diethyl ether, dichloromethane,
tetrahydrofuran, chloroform or N-methylpyrrolidone or a mixture thereof). The
reaction may require cooling or heating, depending on the method used. Further,
the reaction is preferably conducted in the presence of an organic or inorganic
base such as cesium bicarbonate, pyridine, lutidine, picoline, quinoline,
10 diisopropylethylamine and the like. The reaction temperature is preferably from
-100 to 30 °C, and more preferably from -78 to 0 °C. The reaction may require
20 minutes to 24 hours to complete, depending on the reagent chosen.
In process (b), a suitable reagent for activation of an alcohol is
trifluoromethanesulfonyl anhydride (Aldrich). The activation may be carried out
15 in a solvent which does not adversely affect the reaction (e.g. diethyl ether,
dichloromethane, tetrahydrofuran, chloroform or N-methylpyrrolidone or a
mixture thereof). The reaction may require cooling or heating, depending on the
method used. Further, the reaction is preferably conducted in the presence of an
organic or inorganic base such as cesium bicarbonate, pyridine, lutidine,
20 picoline, quinoline, diisopropylethylamine and the like. The reaction
temperature is preferably from -100 to 30 °C, and more preferably from -78 to 0
°C. The reaction may require 20 minutes to 24 hours to complete, depending on
the reagent chosen.
In process (c), a suitable reagent for the formation of an activated alcohol
25 derivative is an aryl chlorofomate, heterocyclic chloroformate, 1,1'-
carbonyldiimidazole, di-(N-succinimidyl)carbonate, or carbonyldi-
(hydroxybenzotriazole). The activation may be carried out in a solvent which
does not adversely affect the reaction (e.g. diethyl ether, dichloromethane,
tetrahydrofuran, chloroform or N-methylpyrrolidone, pyridine or a mixture
30 thereof). The reaction may require cooling or heating, depending on the method
used. Further, the reaction is preferably conducted in the presence of an organic
or inorganic base such as cesium bicarbonate, pyridine, lutidine, picoline,
quinoline, diisopropylethylamine and the like. The reaction temperature is
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preferably from 0 °C to 100 °C. The reaction may require 20 minutes to 24
hours to complete, depending on the reagent chosen.
In process (d), a suitable reagent for the formation of a carbamate is any
suitable amine. The reaction may be carried out in a solvent which does not
5 adversely affect the reaction (e.g. diethyl ether, dichloromethane,
tetrahydrofuran, chloroform or N-methylpyrrolidone, pyridine or a mixture
thereof). The reaction may require cooling or heating, depending on the method
used. Further, the reaction is preferably conducted in the presence of an organic
or inorganic base such as cesium bicarbonate, pyridine, lutidine, picoline,
10 quinoline, diisopropylethylamine and the like. The reaction temperature is
preferably from 0 °C to 100 °C. The reaction may require 20 minutes to 24
hours to complete, depending on the reagent chosen.
In process (e), a suitable reagent for inversion is water. The reaction may
be carried out in a solvent which does not adversely affect the reaction (e.g.
15 dioxane, DMSO, acetonitrile, tetrahydrofuran, or N-methylpyrrolidone, pyridine
or a mixture thereof). The reaction may require cooling or heating, depending on
the method used. The reaction temperature is preferably from 0 °C to 100 °C.
The reaction may require 20 minutes to 24 hours to complete, depending on the
solvent chosen.
20 In process (f), a suitable reagent and solvent for inversion is N,N-
dimethylformamide. The reaction temperature is preferably from 0 °C to 100 °C.
The reaction may require 20 minutes to 24 hours to complete.
In process (g), suitable reagents are H-SR 21 , H-NR 24 R 25 , or
H2NC(S)NH2 and a secondary- or tert-amine base such as morpholine or Hunig's
25 base. The reaction may be carried out in a solvent which does not adversely
affect the reaction (e.g. methylene chloride, dioxane, acetonitrile,
tetrahydrofuran, N,N,N,N,-tetraalkylurea, or N-methylpyrrolidone, pyridine or a
mixture thereof). The reaction temperature is preferably from 0 °C to 100 °C.
The reaction may require 20 minutes to 24 hours to complete.
30 In processes (h), (i), (j), (k), (1), (m), (n) and (o), ether formation may be
carried out using, for example, appropriately substituted alkyl halides in the
presence of KY-zeolite (Onaka, M.; Kawai, M.; Izumi, Y. Chem. Lett. 1983,
1 101), polymeric materials (Kimura, Y.; Kirszensztejn, P.; Regen, S. L. J. Org.
Chem. 1983, 48, 385), nickel-catalysis (Camps, F.; Coll, J.; Moreto, J. M.
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Synthesis 1982, 186; Yamashita. Synthesis 1911, 803), arylalkyl-0-p-
toluenesulfonate (Dewick, P. M. Synth. Commun. 1981, 11, 853), potassium or
sodium alkoxides (Bates, R. B.; Janda, K. D. /. Org. Chem. 1982, 47, 4374),
pyridine or other bases (Chem. Lett. 1978, 57), tetraalkylammonium halide
5 (Miller, J. M.; So, K. H.; Clark, J. H. Can. J. Chem. 1979, 1887), mercury
perchlorate (McKillop, A.; Ford, M. E. Tetrahedron 191 A, 30, 2467), silver
triflate or silver oxide (Kuhn, R.; Low, L; Trischmann, H. Chem. Ber. 1957, 90,
203. Croon, L; Lindberg, B. Acta Chem. Scand., 1959, 13, 593) or a phase
transfer catalyst (McKillop, A.; Fiaud, J.-C; Hug, R. P. Tetrahedron 1974, 30,
10 1379). The ether formation may also be carried out with dialkyl- or
diarylphosphoric acid in the presence of p-toluenesulfonic acid (Kashman, Y. /.
Org. Chem. 1972, 37, 912), with diazo compounds with tin(II) chloride
(Christensen, L. F.; Broom, A. D. J. Org. Chem. 1972, 37, 3398), or with 2,2,2-
trichloroalkanols in the presence of base (Corey, E. J.; Link, J. O. /. Am. Chem.
15 Soc. 1992, 114, 1906; Corey, E. J.; Link, J. O. Tetrahedron Lett. 1992, 33,
343 1). Additionally, ether formation may be accomplished with a suitable
trichloroacetimidate in the presence of an acid catalyst (Wessel, H. P.; Iversen,
T.; Bundle, D. R. J. Chem. Soc. Perk Trans. 1985, 1, 2247.) The ether formation
may be carried out in a solvent which does not adversely affect the reaction (e.g.
20 acetone, dichloromethane, tetrahydrofuran, pyridine, N,/V-dimethylformamide,
ether, acetonitrile, cyclohexane, etc. or a mixture thereof). The reaction may be
conducted above, at, or below ambient temperature.
O-Alkylation may be carried out using substituted alkyl halides,
substituted alkyl trifluoromethanesulfonates, substituted fluorosulfonates, and the
25 like in the presence of an appropriate base such as triethylamine, potassium
fluoride, silver carbonate, silver triflate or silver(I) oxide. The reaction is
performed in an inert solvent such as N,N-dimethylformamide, acetonitrile or
dichloromethane, preferably between -78 °C and 80 °C. Alternatively, alkylation
can be carried out using substituted diazoalkanes, such as diazomethane, ethyl
30 diazoacetate, and the like, in the presence of a metal catalyst, for example
Rh(OAc)2 in an inert solvent such as dichloromethane preferably between -20 °C
and 80 °C.
In process (p), -OCH2-NHC(0)R 24 formation may be carried out by first
forming an -0-CH 2 -C(0)N 3 by activating a -0-CH 2 -C(0)OH in the molecule
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with a chloroformate, such as isobutyl chloroformate, in the presence of a tertiary
amine, such as N-methyl-morpholine or N-methyl-piperidine, and treating with
an azide source, such as sodium azide, hydrazoic acid, trimethylsilylazide, or
tetramethylguanidinium azide. The acyl azide may also be formed directly using
5 diphenylphophorylazide in the presence of a tertiary amine. The reaction
mixture is then heated at from 40 °C to 100 °C for 0.5 to 6 hours, whereupon
R 24 C02H is added and the reaction is heated between 40 °C and 120 °C in a
inert solvent to form -OCH 2 -NHC(0)R 24 .
In process (q), the -0-CH2-NHC(0)NR 24 R 25 formation may be carried
10 out by first forming an -0-CH2-C(0)N3 by activating a -0-CH2-C(0)OH in the
molecule with a chloroformate, such as isobutyl chloroformate, in the presence
of a tertiary amine, such as N-methyl-morpholine or N-methyl-piperidine, and
treating with an azide source, such as sodium azide, hydrazoic acid,
trimethylsilylazide, or tetramethylguanidinium azide. The acyl azide may also
15 be formed directly using diphenylphophorylazide in the presence of a tertiary
amine. The reaction mixture is then heated at from 40 °C to 100 °C for 0.5 to 6
hours, whereupon the amine HNR^R 25 is added at a temperature at from 23 °C
to 100 °C. The reaction is conducted in an inert organic solvent such as diethyl
ether, tetrahydrofuran, 1,4-dioxane, chloroform, methylene chloride, benzene or
20 toluene; alternatively the -0-CH2-NHC(0)NR 24 R 25 moiety may be formed by
alkylation of the C42 hydroxyl group with LG-CH 2 -NHC(0)NR 24 R 25 ,
where LG may be halogen or activated hydroxyl, such as mesylate, triflate,
fluorosulfonate and the like.
In process (r) condensation of an amine with a group of formula -Q-
25 (CH2)iC(0)OH, may be performed using the mixed or symmetrical anhydride of
said acid, the acyl cyanide of the carboxylic acid, or acyl azide of the carboxylic
acid. Alternatively, in a group of formula -O-(CH2)iC(O)OR 20a , where R 20a is
defined as R 2 ^ excluding hydrogen, OR 20a is displaced by NR 24 R 25 , where the
exchange is conducted in an inert solvent, such as dichloromethane, and may be
30 facilitated by A1(CH3>3, Sn[N(Si(CH3)3)2te, a Grignard reagent and the like.
In process (s) condensation of NH(OR 24 )R 25 , where R 24 and R 25 are as
defined above, with a group of formula -0-(CH2)iC(0)OH, may- be performed
using the mixed or symmetrical anhydride of said acid, the acyl cyanide of the
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carboxylic acid, or acyl azide of the carboxylic acid. Alternatively, in a group of
formula -O-(CH 2 )iC(O)OR20a w here R 20a is defined as R 20 excluding
hydrogen, OR 20a is displaced by N(OR 24 )R 25 , where the exchange is conducted
in an inert solvent, such as dichloromethane, and may be facilitated by A1(CH3)3,
5 Sn[N(Si(CH3)3)2]2> a Grignard reagent and the like.
In process (t) condensation of NHR^NR^R 25 , where R 24 and R 25 are as
defined above, with a group of formula -0-(CH2)iC(0)OH, may be performed
using the mixed or symmetrical anhydride of said acid, the acyl cyanide of the
carboxylic acid, or acyl azide of the carboxylic acid. Alternatively, in a group of
10 formula -O-(CH2)iC(O)OR 20a , where R 20a is defined as R 20 excluding
hydrogen, OR 20a is displaced by NR^NR^R 25 , where the exchange is
conducted in an inert solvent, such as dichloromethane, and may be facilitated by
A1(CH3>3, Sn[N(Si(CH3)3)2]2, a Grignard reagent and the like.
In process (u), the -0-CH2-NHC(0)N(OR 24 )R 25 formation may be
15 carried out by first forming an -0-CH2-C(0)N3 by activating a -0-CH2-C(0)OH
in the molecule with a chloroformate, such as isobutyl chloroformate, in the
presence of a tertiary amine, such as N-methyl-morpholine or N-methyl-
piperidine, and treating with an azide source, such as sodium azide, hydrazoic
acid, trimethylsilylazide, or tetramethylguanidinium azide. The acyl azide may
20 also be formed directly using diphenylphophorylazide in the presence of a
tertiary amine. The reaction mixture is then heated at from 40 °C to 100 °C for
0.5 to 6 hours, whereupon the amine HN(OR 24 )R 25 is added at a temperature at
from 23 °C to 100 °C. The reaction is conducted in an inert organic solvent such
as diethyl ether, tetrahydrofuran, 1,4-dioxane, chloroform, methylene chloride,
25 benzene or toluene; alternatively the -0-CH2-NHC(0)N(OR 24 )R 25 moiety may
be formed by alkylation of the C42 hydroxyl group with LG-CH2-
NHC(0)N(OR 24 )R 25 , where LG may be halogen or activated hydroxyl, such as
mesylate, triflate, fluorosulfonate and the like.
In process (v), the -0-CH 2 -NHC(0)NR 24 NR 24 R 2 5 formation may be
30 carried out by first forming an -0-CH2-C(0)N3 by activating a -0-CH 2 -C(0)OH
in the molecule with a chloroformate, such as isobutyl chloroformate, in the
presence of a tertiary amine, such as N-methyl-morpholine or N-methyl-
piperidine, and treating with an azide source, such as sodium azide, hydrazoic
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acid, trimethylsilylazide, or tetramethylguanidinium azide. The acyl azide may
also be formed directly using diphenylphophorylazide in the presence of a
tertiary amine. The reaction mixture is then heated at from 40 °C to 100 °C for
0.5 to 6 hours, whereupon the amine HNR^NR^R 25 is added at a temperature
5 at from 23 °C to 100 °C. The reaction is conducted in an inert organic solvent
such as diethyl ether, tetrahydrofuran, 1,4-dioxane, chloroform, methylene
chloride, benzene or toluene; alternatively the -0-CH2-NHC(0)NR 24 NR 24 R 2 5
moiety may be formed by alkylation of the C42 hydroxyl group with LG-
CH 2 -NHC(0)NR 24 NR 24 R25, where LG may be halogen or activated hydroxyl,
10 such as mesylate, triflate, fluorosulfonate and the like.
In process (w), suitable azide reagents include well-established alkali
metal azides such as sodium or lithium azides (NaN3 or L1N3) in the presence or
absence of crown ethers, more reactive tetraalkylammonium azides (Danishefski,
S. J.; DeNinno, M. P.; Chen, S.-H. /. Am. Chem. Soc. 1988, 110, 3929), a
15 copper-assisted azide reaction (Yamamoto, Y.; Asao, N. /. Org. Chem. 1990, 55,
5303) and a hydrogen azide-amine system (Saito, S.; Yokoyama, H.; Ishikawa,
T.; Niwa, N.; Moriwake, T. Tetrahedron Lett. 1991, 32, 663; Saito, S.;
Takahashi, N.; Ishikawa, T.; Moriwake, T. Tetrahedron Lett. 1991, 32, 667). The
azide displacement reaction may be carried out in a solvent which does not
20 adversely affect the reaction (e.g. chloroform, acetone dichloromethane,
tetrahydrofuran, pyridine, dimethylsulfoxide, N,N-dimethylformamide,
hexamethylphosphoramide, etc. or a mixture thereof). The reaction may be
conducted above, at, or below ambient temperature.
In process (x), the reduction may be carried out catalytically using
25 hydrogen. Suitable catalysts include, but are not limited to platinum catalysts
(e.g. platinum oxide, platinum black), palladium catalysts (e.g. palladium oxide,
palladium on charcoal, palladium black, palladium hydroxide on charcoal,
palladium on calcium carbonate poisoned with lead, palladium on barium
carbonate with quinoline), nickel catalysts (e.g. nickel oxide, Raney nickel),
30 rhodium catalysts (e.g. rhodium on alumina). Reduction may also be carried out
using metal reducing reagents (see Review; Scriven, E. F. V.; Turn bull, K. Chem
Rev. 1988, 88, 321; Patai, S., Ed., "The Chemistry oftheAzido Group"
Interscience Publishers, New York, 1971; Scriven, E. F. V., Ed., "Azides and
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Nitrenes Reactivity and Utility" Academic Press, Inc., New York, 1984) such as
sodium borohydride under phase-transfer conditions, borohydride supported on
an ion exchange resin, lithium aluminum hydride and the like, furthermore, 1,3-
propanedithiol-triethylamine method (Bayley, H.; Staudring, D. N.; Knowles, J.
5 R. Tetrahedron Lett. 1978, 3633), triphenylphosphine (Vaultier, M.; Knouzi, N.;
Carrie, R. Tetrahedron Lett. 1983, 24, 763), and sodium tellurium hydride
(Suzuki, H.; Takaoka, K. Chem Lett. 1984, 1733).
The reduction may be carried out in a solvent which does not adversely
affect the reaction (e.g., alcohols, water, acetone, dichloromethane,
10 tetrahydrofuran, pyridine or Af,N-dimethylformamide or a mixture thereof). The
reaction may be conducted above, at, or below ambient temperature.
In process (y), suitable 7V-acylations may be carried out using the
methods of symmetric carboxylic acid anhydrides, carboxylic acid halides,
mixed carbonic-carboxylic anhydrides, active esters (p-nitrophenylester,
15 trichlorophenyl ester, pentafluorophenyl ester, N-hydroxysuccinimide,
cyanoethyl and the like), and carboxylic acid with suitable condensing reagents
such as DCC (iV^V-dicyclohexylcarbodiimide and its related condensing agents),
DCC-HOBt (N^-dicyclohexylcarbodiimide- 1 -hydroxy benzotriazole),
Woodward reagent K method, A^Af-carbonyldiimidazole and phosphonium
20 containing reagents (e.g. benzotriazolyloxytris[dimethylamino]phosphonium
hexafluorophosphate, A/',N-bis[2-oxo-3-ox-azolidinyl]phosphorodiamidic
chloride, diethylphosphorobromidate, diphenylphosphoryl azide, bromo
tris[dimethylamino]phosphonium hexafluorophosphate, and the like). Suitable
reagents for amide formation include, but are not limited to formyl derivatives,
25 acetyl halides (chloroacetyl, trichloroacetyl, o-nitrophenylacetyl, o-
nitrophenoxyacetyl, acetoacetyl, [N'-dithiobenzyloxycarbonylamino] acetyl and
the like), and substituted propionyl derivatives (3-phenylpropionyl, isobutyryl,
picolinoyl, and the like). Other groups may be found in volume 3 of The Peptides
Gross, E. and Meinhofer, J. Academic Press, 1981 and Protective Groups in
30 Organic Synthesis Greene, T. W. John Wiley & Sons, New York, Chapter 7,
1981. Typically used coupling conditions are described by Gross, E.; Meinhofer,
J. "The Peptides" vol. 3, Academic Press, 1981. The N-acylation may be carried
out in a solvent which does not adversely affect the reaction (e.g. acetone,
dichloromethane, chloroform, tetrahydrofuran, N.N-dimethylformamide,
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dimethylsulfoxide, diethylether, and the like, or a mixture thereof). The reaction
may be conducted above, at, or below ambient temperature.
In process (z), urea formation may be carried out from the following
reactions; reaction with silicon tetraisocyanate or silicon tetraisothiocyanate
5 (Neville, R. G.; McGee, J. J. Can. J. Chem. 1963, 41, 2123), reaction with NJN-
carbonyldiimidazole or A^Af-thiocarbonyldiirnidazole, followed by //-substituted
primary or secondary amines or ammonia (Staab, H. A.; Wendel, K. Org. Synth.
1968, 48, 44), and reaction with phosgene or thiophosgene in the presence of
tert-armne, followed by ^-substituted primary or secondary amines or ammonia.
10 The ureido formation may be carried out in a solvent which does not adversely
affect the reaction (e.g. acetone, toluene, dichloromethane, tetrahydrofuran,
pyridine, A^^V-dimethylformamide, etc. or a mixture thereof). The reaction may
be conducted above, at, or below ambient temperature.
In process (aa), N-sulfonylation may be carried out using substituted
15 sulfonylhalides in the presence of suitable terr-amines such as trialkylamine,
pyridine, and the like (Remers, W. A.; Roth, R. H.; Gibs, G. J.; Weiss, M. J. /.
Org. Chem. 1971, 36, 1232). Suitable reagents include, but are not limited to
benzenesulfonyl halide, p-methyoxybenzenesulfonyl halide, 2,4,6-
trimethylbenzenesulfonyl halide, toluenesulfonyl halide, benzyl sulfonyl halide,
20 p-methoxybenzylsulfonyl halide, trifluoromethylsulfonyl halide,
phenacylsulfonyl halide, and the like. Some other representative groups may be
found in volume 3 of The Peptides, Gross, E. and Meinhofer, J. Academic Press,
1981 and Protective Groups in Organic Synthesis, Greene, T. W. John Wiley &
Sons, New York, Chapter 7, 1981. The iV-aryl- or alkylsulfonylation may be
25 carried out in a solvent which does not adversely affect the reaction (e.g.,
acetone, dichloromethane, tetrahydrofuran, pyridine or MN-dimethylformamide
or a mixture thereof). The reaction may be conducted above, at, or below
ambient temperature.
In process (bb), TV-carbamate formations may be carried out using
30 common protecting groups for amino group such as, but not limited to
methylcarbamates (cyclopropylmethyl, 9-fluorenylmethyl, and the like),
substituted ethylcarbamates (2,2,2-trichloroethyl, 2-phosphonoethyl, 2-
methylthioethyl, and the like), substituted propyl and isopropylcarbamates (1,1-
dimethylpropynyl, 1 -methyl- l-(4-biphenylyl)ethyl, ter t-butyl, phenyl,/?-
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nitrobenzyl, 8-quinolyl, 7V-hydroxypiperidinyl, benzyl, dimethoxybenzyl, 9-
anthrylmethyl, 1-adamantyl, cyclohexyl, tert-amyl, cinnamoyl, isobutyl, N -p-
phenylaminothiocarbonyl, TV'-piperidinylcarbonyl, diphenylmethyl, and the like).
Preparations of N-carbamates and other groups may be found in volume 3 of The
5 Peptides, Gross, E. and Meinhofer, J. Academic Press, 1981 and Protective
Groups in Organic Synthesis, Greene, T. W. John Wiley & Sons, New York,
Chapter 7, 1981. The TV-carbamate formation may be carried out in a solvent
which does not adversely affect the reaction (e.g., acetone, dichloromethane,
tetrahydrofuran, pyridine or N^V-dimethylformamide or a mixture thereof). The
10 reaction may be conducted above, at, or below ambient temperature.
In process (cc), N-sulfenamides may be prepared from an amine and a
sulfenyl halide (Davis, F. A.; Nadir, U. K. Org. Prep. Proc. Int. 1979, 77, 33;
Kobayashi, T.; lino, K.; Hiraoka, T. /. Am. Chem. Soc. 1977, 99, 5505; Zervas,
L.; Borovas, D.; Gazis, E. /. Am. Chem. Soc. 1963, 55, 3660). Suitable reagents
15 include, but are not limited to benzenesulfenyl halide, o-nitrobenzenesulfenyl
halide, 2,4-dinitrosulfenyl halide, pentachlorobenzenesulfenyl halide, 2-nitro-4-
methoxybenzenesulfenyl halide, triphenylmethylsulfenyl halide, and the like.
Other groups may be found in volume 3 of The Peptides, Gross, E. and
Meinhofer, J. Academic Press, 1981 and Protective Groups in Organic
20 Synthesis, Greene, T. W. John Wiley & Sons, New York, Chapter 7, 1981. The
yV-sulfenylation may be carried out in a solvent which does not adversely affect
the reaction (e.g., acetone, dichloromethane, tetrahydrofuran, pyridine or N,N-
dimethylformamide or a mixture thereof). The reaction may be conducted above,
at, or below ambient temperature.
25 In process (dd), -N=C=0 may be prepared from an amine and oxalyl
chloride, phosgene, diphosgene or triphosgene with or without the presence of a
base (Weisenfeld, R.B., J. Org. Chem., 51 (13): 2434-2436, 1986; Eckert, H.,
Forster, B., Angew. Chemie, IE, 26(9): 894-895, 1987; Arnold-Stanton, R.,
Lemal, D.J.,7. Org. Chem., 56(1), 146-151, 1991; Danda, H., Chino, K., Wake,
30 S., Chem. Exp., 6(4), 261-264, 1991). Suitable base for the reaction are
triethylamine, diisopropylethylamine, pyridine, 2,6-lutidine etc.
The reaction may be carried out in a solvent which does not adversely
affect the reaction (e.g. ether, toluene, dichloromethane, chloroform,
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chlorobenzene etc.). The reaction may be conducted above, at, or below room
temperatue.
In process (ee), a -SePh group may be prepared by selective displacemnet
of an -OS(0)2F or -OS(0)2CF3 with benzeneselenol in the presence of a base.
5 Suitable bases for the reaction are triethylamine, diisopropylethylamine,
pyridine, 2,6-lutidine etc. The reaciton may be carried out in a solvent which
does not adversely affect the reaction (e.g. ether, toluene, dichloromethane,
chloroform, chlorobenzene etc.). The reaction may be conducted above, at, or
below room temperatue.
10 In process (ff), a -Se(0)Ph group may be prepared by selective oxidation
of an -Se-Ph group with appropriate peroxides in the presence of a base.
Suitable peroxides are hydrogen peroxide, tirfluoroperacetic acid,
peracetic acid, or m-chlorperbenzoic acid, etc. Suitable base for the reaction are
sodium bicarbonate, potassium bicarbonat, or cesium biccarbonate, etc. The
15 reaciton may be carried out in a solvent which does not adversely affect the
reaction (e.g. ether, toluene, dichloromethane, chloroform, chlorobenzene etc.).
The reaction may be conducted above, at, or below room temperatue.
In process (gg), a compound of formulae IV, where one of R 8 and R 9
with one of R 18 and R 19 taken together form a bond, the others of R 8 , R 9 , Rl8
20 and R 19 are hydrogen, by selective 1 ,2-eliminaion of an H-OSePh group in a
corresponding compound containing an -Se(0)Ph group with or without the
presence of base.
Suitable base for the reaction are sodium bicarbonate, potassium
bicarbonat, or cesium biccarbonate, etc. The reaciton may be carried out in a
25 solvent which does not adversely affect the reaction (e.g. ether, toluene,
dichloromethane, chloroform, chlorobenzene etc.). The reaction may be
conducted at or above room temperatue.
In process (hh), selective oxidation of a double bond to form a 1,2-diol
may be carried out using tertiary amine /V-oxide-osmium tetraoxide
(VanRheenen, V., Kelly, R. C. and Cha, D. Y. Tetrahedron Lett., 1976, 25,
1973-1976; Fraser-Reid, B., Molino, B. F., Magdzinski, L. and Mootoo, D. R. /.
Org. Chem., 1987, 52, 4505-451 1); pyridine-osmium tetraoxide (Cimino, G.,
Gavagnin, M., Sodano, G., Spinnella, A., Strazzullo, G., Schmitz, F. J. and
Yalamanchili, G. J. Org. Chem., 1987, 52, 2301-2303.). chiral amine-osmium
30
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tetraoxide (Yamada, T. and Narasaka, K.-Chem. Lett., 1986, 131; Tokles, M. and
Snyder, J. K. Tetrahedron Lett., 1986, 27, 3957).
The reaction may be carried out in a solvent which does not adversely
affect the reaction (e.g., diethylether, dichloromethane, tetrahydrofuran,
5 acetonitxile, chloroform or A^^V-dimethylformamide or a mixture thereof). The
reaction may require cooling or heating, depending on the method chosen.
In process (ii), protection and derivatization for 1,2-diol may be carried
out as cyclic acetals, cyclic ketals, cyclic ortho esters, cyclic boronates, cyclic
carbonates, or as cyclic silyl derivatives. Suitable cyclic acetal and cyclic ketal
10 formations may be carried out using a reaction of the diol and a carbonyl
compound in the presence of an acid catalyst ( Fletcher, Jr. H. G Methods
Carbohydr. Chem., 1963, 77, 307; Amarnath, V. and Broom, A. D. Chem. Rev.,
1977, 77, 183; Reese, C. B. Tetrahedron, 1978, 34, 3143 ; Clode, D. M. Chem.
Rev. 1979, 79, 491 ; Hanessian, S., Chung, G. Y., Lavallee, P. and Pernet, A. G.
15 /. Am. Chem. Soc, 1972, 94, 8929; Yuceer, L. Carbohydr. Res., 1977, 56, 87.).
Cyclic ortho ester formation, including cyclic orthoformates, may be carried out
using a wide variety of reagents, but not limitted to tetramethyl orthocarbonate-
p-toluenesulfonic acid method ( Niaz, G. R. and Reese, C. B. /. Chem. Soc.
Chem. Commun., 1969, 552), or acid catalized transketalization ( Reese, C. B.
20 Tetrahedron, 1978, 34, 3143; Amarnath, V. and Broom, A. D. Chem. Rev., 1977,
77, 183; Ahmad, M., Bergstrom, R. G., Cashen, M. J., Kresge, A. J., MaClelland,
R. A. and Powell, M. F. /. Am. Chem. Soc, 1977, 99, 4827). Cyclic carbonate
may be prepared from 1,2-diol and phosgene or a chloroformate (Hough, L.,
Priddle, J. E. and Theobald, R. S. Adv. Carbohydr. Chem., 1960, 75, 91-158 ;
25 Amarnath, V. and Broom, A. D. Chem. Rev., 1977, 77, 183; Letsinger, R. L. and
Ogilvie, K. K. J. Org. Chem., 1967, 32, 296 ; Kutney, J. P. and Ratcliffe, A. H.
Synth. Commun., 1975, 5, 47.). Cyclic silyl derivatives of 1,2-diol may be
prepared from the reaction using bis-(rer/-butyl)dichlorosilane-triethylamine
(Tetrahedron Lett., 1981, 22, 4999), or diisopropylsilyl
30 bis(trifluotomethanesulfonate)-te/t- amine (Tetrahedron Lett., 1982, 23, 4871),
and the like. Cyclic boronates formation may be carried out using following
references (Ferrier, R. J. Adv. Carbohydr. Chem. Biochem., 1978, 35, 31-80;
Frechet, J. M. J., Nuyens, L. J. and Seymour, E. J. Am. Chem. Soc, 1979, 707,
432).
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The reaction may be carried out in a solvent which does not adversely
affect the reaction (e.g., diethylether, dichloromethane, tetrahydrofuran,
acetonitrile, chloroform or N^V-dimethylf ormamide or a mixture thereof). The
reaction may require cooling or heating, depending on the method chosen.
5 In process (jj), suitable reducing agents are trialkylsilanes. Suitable acids
are toluenesulfonic acid, trifluroacetic acid, borotrifluoride etherate etc. The
reaction may be carried out in a solvent which does not adversely affect the
reaction (e.g., diethylether, dichloromethane, tetrahydrofuran, or chloroform or a
mixture thereof). The reaction may be conducted at -50 to 0 °C.
10 In process (kk), suitable alkylating agents are allyltrimethylsilane or alkyl
alcohol. Suitable acids are toluenesulfonic acid, trifluroacetic acid,
borotrifluoride etherate etc. The reaction may be carried out in a solvent which
does not adversely affect the reaction (e.g., diethylether, dichloromethane,
tetrahydrofuran, or chloroform or a mixture thereof). The reaction may be
15 conducted at -50 to 0 °C.
In process (11), a suitable reagent for activation of the alcohol of formula
is fluorosulfonyl anhydride (prepared according to the procedure described by S.
Kongpricha, W.G. Preusse and R. Schwarer, in Inorganic Synthesis, 1968, 11,
pl5 1-155) or trifluoromethanesulfonyl anhydride. The activation may be carried
20 out in a solvent which does not adversely affect the reaction (e.g. diethyl ether,
dichloromethane, tetrahydrofuran, chloroform or N-methylpyrrolidone or a
mixture thereof). The reaction may require cooling or heating, depending on the
method used. Further, the reaction is preferably conducted in the presence of an
organic or inorganic base such as cesium bicarbonate, pyridine, lutidine,
25 picoline, quinoline, diisopropylethylamine and the like. The reaction
temperature is preferably from -100 to 30 °C, and more preferably from
-78 to 0 °C. The reaction may require 20 minutes to 24 hours to complete,
depending on the reagent chosen.
A suitable reagent for the dehydration of an activated alcohol is silica gel
30 or triethylamine. The reaction may be carried out in a solvent which does not
adversely affect the reaction (e.g. diethyl ether, dichloromethane,
tetrahydrofuran, chloroform or toluene or a mixture thereof). The reaction may
require cooling or heating, depending on the method used. The reaction
temperature is preferably from -100 to 30 °C, and more preferably from -20 to 0
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°C. The reaction may require 20 minutes to 24 hours to complete, depending on
the conditions chosen. The hydrolysis of the dehydrated enol ether *
may be carried out in dilute aqueous acid at room temperature.
In process (mm), a suitable acid for the rearrangement of the activated
5 alcohol is silica gel. The reaction may be carried out in a solvent which does not
adversely affect the reaction (e.g. diethyl ether, dichloromethane,
tetrahydrofuran, chloroform or toluene or a mixture thereof). The reaction may
require cooling or heating, depending on the method used. The reaction
temperature is preferably from -100 to 30 °C, and more preferably from -20 to 0
10 °C. The reaction may require 20 minutes to 24 hours to complete, depending on
the conditions
It should be noted that numerous asymmetric centers may exist in the
compounds of the present invention. Except where otherwise specified, the
present invention contemplates the various stereoisomers and mixtures thereof.
15 It should also be noted that certain variable elements of the structural formulae
herein, such as the radicals R 11 , R 20 , R 24 , R 25 , R 26 and R 27 or the subscript
integers m and s , may appear more than once in a particular formula. In such
instances, it is intended that, within a single formula, the values of these
variables may be the same or different at each occurrence.
The present invention can be illustrated by the following non-limiting,
representative examples. In the following examples, unless states otherwise,
RlOa = -OCH 3 and R 10b = H.
The following abbreviations are used: DDQ for 2,3-dichloro-5,6-dicyano-
25 1,4-benzoquinone, ED AC for l-ethyl-3-(3'-dimethylarnino)-propylcarbodiirnide,
EtOAc for ethyl acetate, EtOH for ethanol, HOBt for 1-hydroxybenzotriazole,
and MeOH for methanol.
Example 1
30 Formula VI: R l = methyl: R 2 - = -H: R2. = -OH: R 4 - and Rl taken together = O:
R fi and Rl taken together = O: X and Y taken together = O: R = F: R2 = H
20
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Fluorosulfonyl anhydride (0.17 g, in 1 mL of dry CH2CI2) was added
into a stirred solution of rapamycin (0.457 g) and 2,6-lutidine (0.22 g) in dry
dichloromethane (5 mL) at -70 °C. After being stirred at -70 °C for 1 hour, the
reaction mixture was partitioned between ether and ice-cold 0.IM hydrochloric
5 acid. The organic phase was washed once with saturated brine, dried over
magnesium sulfate and filtered through silica gel (2 g) eluting with ether. The
solvent was removed in vacuo, and the product was stored in the freezer.
Example 2
10 Formula VTT: R l= methvl: R2 = _H: R l = -OH: R4 an d R 5 - taken together = O: R6
and R 7 - taken together = O: X and Y taken toeether = O:
R & = -QCr=OVOrr)-NilTn-phenv1V R2 = _R
4-Nitrophenyl chloroformate (0.5 g) was added into a stirred solution of
rapamycin (0.9 g) in dry pyridine (2 mL) at room temperature. After being
15 stirred at 40-50 °C for 0.5 hour, the reaction was cooled to 0 °C and partitioned
between ether and ice-cold 0.4 N hydrochloric acid. The organic phase was
washed once with brine, dried over magnesium sulfate and solvent removed in
vacuo. The product was purified by silica gel chromatography (20 g) eluting
with 20% acetone/hexanes to afford 0.72 g of the title compound. MS (FAB)
20 m/z: M+K= 1117.
Example 3
Formula VII: R-i= methvl: R2 _ -H: R 2 = -OH: Rl and R£ taken together = O-
RAand R l taken together = O: X and Y taken together = O:
25 R S = -OCr=OVmomholine: R 9 = -H
To the compound resulting from Example 2 (514.5 mg) dissolved in 3.5
mL of anhydrous dichlormethane at 0 °C was added morpholine (250 |jL). The
reaction mixture was allowed to warm to room temperature and stirred for 2
hours. The reaction mixture was purified by silica gel chromatography (70 g)
30 eluting with 25% acetone/hexanes to give 343.2 mg of the title compound, m.p.
115-199 °C. MS (FAB) m/z: M+K= 1065.
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Example 4
Formula VII: Rl= methvl: R2 = -H: R2 = -OH: Ri and R 5 - taken together = O: R6
5 and Rl taken together = O: X and Y taken together = O:
R & = -OCf=OVOrN-succinimidvlV. R?- = -H
The title compound is prepared from rapamycin and di-(N-succinimidyl)-
carbonate in pyridine according to the procedure described in Example 2.
Example 5
Formula VII: Rl= methvl: R2 = -H: R3- = -OH: Ri and R5 taken together = O:
R 6 and Rl taken together = O: X and Y taken together = O:
R & = -Oq=OWN-triazoleV. R& = -H
The title compound is prepared from rapamycin and 1,1'-
carbonyldi(l,2,4-triazole) in pyridine according to the procedure described in
Example 2.
10
15
Example 6
Formula VII: Rl= methvl: R2 = -H: R2 = -QH: Rl and R5 taken together = O:
20 Rfi and Rl taken together = O: X and Y taken together = O:
R £ = -QC(=OUN-imidazole"): R9 = -H
The title compound is prepared from rapamycin and 1,1'-
carbonyldiimidazole in pyridine according to the procedure described in
Example 2.
25
Example 7
Formula VII: Rl^ methvl: R2 = -H: Rl - -OH: R4 and Ri taken together = O: R&
and Rl taken together = O: X and Y taken together = O:
R8 = -Oa=OVO('hvdroxv-benzotriazole'): R?- - -H
30 The title compound is prepared from rapamycin and 1, l'-carbonyldi-
(hydroxybenzotriazole) in pyridine according to the procedure described in
Example 2.
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Example 8
Formula VII: Rl= methvl: R2 = -H: R2 = -OH: Ri and R5 taken together = O:
5 R 6 and Rl taken together = O: X and Y taken together - O:
R & = -OCf=OVr>iperidine: R2 = -H
The title compound is prepared from the compound resulting from
Example 2 and piperidine according to the procedure described in Example 3.
10 Example 9
Formula I: Rl= methvl: R2 = -H: R3. = -OH: R4 and R^ taken together = O:
R6 and RZ taken together = O: X and Y taken together = O; R& = -H;
r £ = -Q-formvl
The title compound of Example 1 is dissolved in N,N-
15 dimethylformamide and stirred at room temperature overnight. The reaction
mixture is partitioned between ether and water. The organic phase is washed
once with brine, dried over magnesium sulfate, and solvent removed in vauco.
The product is purified by silica gel chromatography eluting with 30%
acetone/hexanes.
20
Example 10
Formula I: Rl= methvl: R2 = -H: Rl = -OH: R4 and Rl taken together = O:
R 6 and Rl taken together = O: X and Y taken together = O: R& = -H: R£ - -OH
To a solution of rapamycin (505.4 mg) in 4 mL of methylene chloride
25 cooled to -78 °C was added 140 fxL of 2,6-lutidine followed by 100 |J,L of
(FS 02)20 in 1 mL of methylene chloride. The reaction mixture was stirred at
-78 °C for 15 minutes after the addition was complete. The reaction mixture was
partitioned between ether and 0.1 N HC1. The organic layer was washed with 20
mL of water and 20 mL of saturated NaCl solution, dried over magnesium
30 sulfate and passed through a silica gel plug eluting with cold ether. The solvent
was removed in vacuo, and the residue was dissolved in 10 mL of a 1:1 mixture
of THF and DMSO. After stirring at room temperature for 10 minutes, the
reaction mixture was stored in the refrigerator for 2 days. Water (2 mL) was
added, and the reaction mxiture was stirred at room temperature for 1 hour. A
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solution was 500 mg of NaHC03 in water (50 mL) was added, and the mixture
was extracted with Et20 (3 x 70 mL). The combined organic extracts were
washed with 50 mL of dilute NaHC03 solution, 50 mL of water, and 50 mL of
saturated NaCl solution, dried over MgSC>4 and concentrated in vacuo. The
5 residue obtained was chromatogrpahed on a silica gel (15 g) column eluting with
4% isopropanol in dichlormethane to give 271 mg of the title compound, m.p.
90-93 °C. MS (FAB) m/z: M+K= 952. Selected CMR (CDC1 3 ): 215.2, 208.1,
192.8, 169.7, 169.3, 166.7, 140.5, 140.1, 136.0, 135.7, 133.6, 133.3, 130.2,
129.5, 129.0, 126.7, 126.4, 98.7, 98.5, 86.4, 84.9, 84.3, 80.6, 77.2, 75.6, 67.8,
10 67.2, 65.5, 59.3, 59.0, 56.4, 55.9, 51.3, 46.5, 46.0, 44.2, 41.4, 40.7, 40.2, 39.0,
38.7, 35.6, 35.2, 34.4, 33.8, 33.1, 32.9, 32.4, 31.4, 30.9, 29.6, 27.2, 27.1, 25.3,
24.4, 21.5, 20.7, 16.3, 16.2, 16.0, 15.9,13.7, 13.2 and 10.2.
Example 1 1
15 Formula I: Ri= methyl: R2 = -H: Rl = -OH: RA and Rl taken together = O:
R 6 and Rl taken together = O; X and Y taken together = O: R& = -H:
R £ = -QC(=OVO(p-Nitro-phenvn
The title compound is prepared from the compound resulting from
Example 10 and 4-nitophenyl chloroformate according to the procedure
20 described in Example 2.
Example 12
Formula I: Rl= methyl: R2 = -H: R2. = -OH: RA and R5- taken together = O:
R 6 and Rl taken together = O: X and Y taken together = O: R& = -H:
25 R 2 - -OC(=Q)-morpholine
The title compound is prepared from the compound resulting from
Example 1 1 and morpholine according to the procedure described in Example 3.
Example 13
30 Formula VI: RL= methyl: R2 = -H: R2 = -OH: Rl and Rl taken together = O:
Rfi and R l taken together = O: X and Y taken together = O: R2=H; R = -CF^
Trifluoromethanesulfonyl anhydride (0.2 g) in 1 mL of dry-CH2Cl2 was
added into a stirred solution of rapamycin (0.457 g) and 2,6-lutidine (0.22 g) in
dry dichloromethane (5 mL) at -70 °C. After being stirred at that temperature for
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1 hour, the reaction mixture was partitioned between ether and ice-cold 0.1N
hydrochloric acid. The organic phase was washed once with saturated brine,
dried over magnesium sulfate and filtered through silica gel (2 g) eluting with
ether. The solvent was removed in vacuo, and the product was stored in the
5 freezer.
Example 14
Formula I: Rl= methyl: RS = -H: R3. = -OH: Rl and Ri taken together = O:
R 6 and Rl taken together = O: X and Y taken together = O: R& = -H:
10 R 2 = -OS(OV>F
The title compound is prepared from the compound resulting from
Example 10 and fluorosulfonyl anhydride according to the procedure described
in Example 1.
15 Example 15
Formula I: Rl= methyl: R2 = -H: R3. - -OH: Rl and R5. taken together = O:
R 6 and Rl taken together = O: X and Y taken together = Q; R& = -H:
R Z = -OS(0) 1 CF 1
The title compound is prepared from the compound resulting from
20 Example 10 and trifluoromethanesulfonyl anhydride according to the procedure
described in Example 1 .
Example 16
Formula V: Rl= methyl: R2 = -H: Rl = -OH: Rl and R5 taken together = O:
25 R £ and Rl taken together = O: X and Y taken together = O:
R S = -OCr=OVNMerOH > ): R 9 = -H
The title compoundwas prepared from the compound resulting from
Example 2 and N-methyl hydroxylamine according to the procedure described in
Example 3.
30
Example 17
Formula V: Rl= methvl: R2 - -H: Rl = -QH: Rl and R 5 taken together = O:
R & and R2 taken together = O: X and Y taken together = O:
R8 = -Oa=Q>NMerOMe-): R2 _ _ H
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To N,0-dimethylhydroxylamine hydrochloride 449.8 mg, 4.6 mmol) was
added pyridine (5 mL), and the mixture was stirred at room temperature for 1
hour. To this solution was added the compound resulting from Example 2 (826.2
mg, 0.701 mmol) at 0 °C under nitrogen. The reaction mixture was stirred at
5 room temperature overnight. The reaction mixture was partitioned between 0.5
N HC1 and Et2C The organic phase was washed with saturated NaCl solution,
dried over MgS04 and passed through a short column of silica gel (10 g). The
partially purified compound was further purified by HPLC (Rainin Microsorb
silica gel) eluting with 75% acetone in hexane to afford the title compound, m.p.
10 105-109 °C. MS (FAB) mlr. M+K= 1039. Selected CMR (CDCI3): 215.5,
208.1, 207.6, 192.5, 169.8, 169.2, 166.8, 156.9, 140.8, 140.2, 136.1, 135.5,
133.7, 133.4, 130.1, 130.0, 129.6, 129.3, 126.7, 126.4, 98.5, 86.5, 84.9, 84.4,
81.1, 78.1, 77.2, 75.5, 67.8, 67.2, 61.5, 59.3, 57.6, 56.2, 55.9, 51.3, 46.6, 46.1,
44.2, 41.4, 40.7, 40.2, 38.9, 38.3, 36.1, 35.6, 35.1, 34.6, 33.8, 33.3, 33.0, 32.9,
15 31.6, 31.3, 30.1, 27.9, 27.3, 27.0, 25.3, 24.3, 22.6, 21.7, 21.5, 20.7, 16.2, 16.1,
15.9, 15.0, 14.1, 13.8, 13.1 and 10.2.
Example 18
Formula V: Rl= methvl: R2 = -H: R2 = -OH: R4 and R5 taken together = O:
20 R & and Rl taken together = O: X and Y taken together = O;
R & - -QC(=OVNHrOBnV. Rg = -H
The title compound is prepared from the compound resulting from
Example 2 and
O-benzylhydroxylamine according to the procedure described in Example 3.
25
Example 19
Formula VII: Rl= methvl: R2 = -H: R2 = -OH: R4 and taken together = O:
R 6 and R^ taken together = O; X and Y taken together = O:
r8 - -QC(=OV( , N-methvlpiperazineV. R^ = -H
30 The title compound is prepared from the compound resulting from
Example 2 and
N-methyl piperazine according to the procedure described in Example 3.
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Example 20
Formula I: Rl = methyl; R2 _= -H; R3 - = -QAc: R4 and R l taken together = O:
5 R^ and R l taken together = O: X and Y taken together = O: Rg = -OH: RS = -H
The title compound is prepared according to EP 0507556 (Example 4).
Example 21
Formula I: Rl= me thyl; R2 - = -H: R 2 = -O-Ctert-hntvldimethvlsilvlV
10 R ~ and R5 taken togeth er = O: R6 and Rl taken together = O:
X and Y taken together = O: R S = -O-ftert-hiitvldimethvlsilvn: R2 = -H
The title compound is prepared from rapamycin according to EP 0507556
(Example 4).
15 Example 22
Formula I: Rl= methyl; R2 _= -H; R l = -QH: R± and R i taken together = O-
R£ and Rl taken together = NNMeo: X and Y taken together = O: R£ = -OH-
R & = -H.
The title compound is prepared from rapamycin according to EP 0507556
20 (Example 1).
Example 23
Formula I: Ri= met hyl: R2 =jH; R l = -QH: R4 and R l taken together = O-
R£ and R2 taken together = NNMeo- X and Y taken together = O- R& = -H:
25 R 2 = -QH
The title compound is prepared from the compound resulting from
Example 10 (42-epi-rapamycin) and N,N-dimethylhydrazine according to the
procedure described in Example 5 of U.S. patent No. 5,120,726, which is
incorporated herein by reference.
30
Example 24
F ormula I: Rl= methyl; R2 = -H: Rl = -QH: Rl and R l taken together = O;
R£ and RZ taken together = N-OMe: X and Y taken together = O- R 8 = . H -
R g - -OH
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The title compound is prepared from rapamycin and O-
methylhydroxylamine according to the procedure described in Example 5 of U.S.
patent 5,120,726 and UK Patent GB 2,247 ,017A which are incorporated herein
by reference.
5
Example 25
Formula I: Rl= methvl: R2 = -H: Rl = -O-ftert-butvldimethvlsilvD:
R 4 and R 5 - taken together = O: R6 and Rl taken together = O:
X and Y taken together = O: R& = -OH: Ri = -H.
10 Two equivalents of 48% aquous HF in acetonitrile is added dropwise into
a stirred solution of the compound resulting from Example 21 in acetonitrile at
0 °C. After being stirred at that temperature for 1 hour, powdered sodium
bicarbonate is added and stirred for another 0.5 hour. The solids are filtered off
and the product is purified by silica gel chromatography.
15
Example 26:
Formula I: Rl= methvl: R2- - -H: R2. = -OH: Rl and R 5 - taken together = O:
R £ and R?- taken together = N-OMe: X and Y taken together = O: R& = -H;
R9 = -QS(Q) 2 F
20 The title compound is prepared from the compound resulting from
Example 24 and fluorosulfonyl anhydride according to the procedure described
in Example 1.
Example 27
25 Formula VI: Rl= methvl: R2 = -H: R^ = tert-butvldimethvlsiloxv:
R l and R 5 - taken together = O: R6 and RZ taken together - O:
X and Y taken together = O: R = F: R2=H
The title compound is prepared from the compound resulting from
Example 25 and fluorosulfonyl anhydride according to the procedure described
30 in Example 1 .
-87-
Example 28
Formula VT: Rl= methyl; R2 =JiEA.=^QA£L£^d taken together = O-
RAand R2 taken together = O; X and Y taken together = O; R = F: R2 =H
The title compound is prepared from the compound resulting from
Example 20 and fluorosulfonyl anhydride according to the procedure described
in Example 1.
Example 29:
Formula T: R% methMlR^^HiRl^OHLR4 and R l taken together = O-
R6and_R2 taken together = N-OM e: X and Y taken together = O; T?£ = .H-
R£ = -OC(=OV Ofn-Nirm-p hP.n Y n
The title compound is prepared from the compound resulting from
Example 24 and
4-nitrophenyl chloroformate according to the procedure described in Example 2.
Example 30
Formula VTT: Rl= methyl; R2 =^& R l = -Q-ftert-hntvldWtr, y l g n y iv
BA_and R5 taken together = O; p6 and R 7 taken together = n ;
X and Y taken toget her = O R£ = -OCr=OVrUp-Nirro_ D henvn- R£
The title compound is prepared from the compound resulting from
Example 25 and
4-nitrophenyl chloroformate according to the procedure described in Example 2.
Example 3 1
Formula VTT: R l^jm^cL^^^^QA^jffid R l taken together = n-
BAand R2 taken together = O: X an H Y taken together = n-
R8 = -OCf=OVn-r r - Nitro-r)hRnvlV R9 = _h
The title compound is prepared from the compound resulting from
Example 20 and
4-nitrophenyl chloroformate according to the procedure described in Example 2.
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Example 32
Formula VII: Rl= methvl: R2 = -H: Rl = -OH: R4 and R5 taken together = O:
5 R & and Rl taken together = N-OMe: X and Y taken together = O:
R £ = -QCr=OVmorpholine: R2 = -H
The title compound is prepared from the compound resulting from
Example 29 and morpholine according to the procedure described in Example 3.
10 Example 33
Formula VII: Rl= methvl: R2 = -H: Rl = -O-ftert-butvldimethvlsilvl): Ri and Rl
taken together = O: R6 and RZ taken together = O: X and Y taken together = O:
R S = -QCf=Cy>-mornho1ine: R2 = -H
The title compound is prepared from the compound resulting from
15 Example 30 and morpholine according to the procedure described in Example 3.
Example 34
Formula VII: Rl= methvl: R2 = -H: Rl = -OAc: Rl and RS. taken together = O:
R 6 and RZ taken together = O: X and Y taken together = O:
20 R g = -OC(=OVmorpholine: R2 = -H
The title compound is prepared from the compound resulting from
Example 31 and morpholine according to the procedure described in Example 3.
Example 35
25 Formula IVc: Rl= methvl: R2 = -H: Rl = -OH: R4 and R5. taken together = O:
R 5 and Rl taken together = O; X and Y taken together = O:
R & and R2 taken together = O
Silica gel (25 g) was added to a solution of the compound resulting from
Example 13 (prepared from 0.53 g of rapamycin) in ether at 0 °C. The solvent
30 was then removed in vacuo, and the resulting powder was refrigerated for 8 days
at 8 °C. The product on silica gel was eluted with acetone and the solvent
removed in vacuo. The crude product was purified by HPLC (Rainin Microsorb
silica gel) eluting with 30% acetone/ hexanes. MS (FAB) m/z: M+K= 920.
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Example 36
Formula IVa: Ri= methvl: R2- = -H: R2 = -OH: Ri and R5. taken together = O;
5 R 6 and Rl taken together = O: X and Y taken together = O
Silica gel (25 g) was added to a solution of the compound resulting from
Example 13 (prepared from 0.53 g of rapamycin) in ether at 0 °C. The solvent
was then removed in vacuo, and the resulting powder was refrigerated for 8 days
at 8 °C. The product on silica gel was eluted with acetone and solvent removed
10 in vacuo. The crude product was purified by HPLC (Rainin Microsorb silica gel)
eluting with 30% acetone/ hexanes. MS (FAB) mlz: M+K= 934.
Example 37
Formula IVh: R l= methvl: R2 = -H: R2 = -OH: Rl and R 5 taken together = Or
15 R6_and R l taken together = O: X and Y taken together = O: R& = Rl& = -H:
R 2 and Ri S . taken together form a bond
The title compound was isolated from the reaction mixture on silica gel
of Example 36. MS (FAB) mlz: M+K= 934.
20 Example 38
Formula II: R l= methvl: R2 = -H: R2l = -OH: Rl and Rl taken together = O:
R£ and R 2 taken together = O: X and Y taken together = O: R£ = _h.
R 2 = -S-r2'-imidazole^
To a solution of rapamycin (838 mg, 0.917 mmol) in 5 mL of methylene
25 chloride was added 450 |_iL of 2,6-lutididine at -78 °C followed by (FS02)20
(200 |JL). The reaction mixture was stirred for 20 minutes under a nitrogen
atmosphere and then 204 mg of 2-mercaptoimidazole in 5 mL of THF was
added. The reaction mixture was allowed to warm to room temperature and
stirred overnight under nitrogen. The reaction mixture was partititioned between
30 150 mL of water and a mixture of 21 : 1 EtOAc and Et20. The aqueous phase
was extracted with two 100 mL portions of the organic solvent mixture. The
combined organic extracts were washed twice with water and once with saturated
sodium chloride solution, dried over MgS04 and concentrated in vacuo. The
residue was purified on a silica gel column eluting with 1 : 1 acetone-hexane to
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give 380 mg of partially purified material which was further purified by HPLC
eluting with 5% isopropanol in methylene chloride, m.p. 122-126 °C. MS
(FAB) m/z: M+K= 1034.
5 Example 39
Formula II: Rl= methyl: R2 = -H: R2 = -OH: Ri and R£ taken together = O:
R 6 and Rl taken together = O: X and Y taken together = Q: R& = -H:
R 2 = -S-(2'-N-methvl-imidazole')
To a solution of rapamycin (639 mg, 0.699 mmol) in 10 mL of methylene
10 chloride was added 250 of 2,6-lutididine at -78 °C followed by (FS02)20
(160 |iL). The reaction mixture was stirred for 20 minutes under a nitrogen
atmosphere and then partitioned between ether and 0.1N HC1. The organic
phase was passed through a silica gel plug eluting with Et20. This activated
intermediate was dissolved in methylene chloride (8 mL), cooled to -78 °C, and
15 treated with 2,6-lutidine (250 \xL) followed by l-methyl-2-mercaptoimidazole
(171.4 mg). The reaction mixture was stirred under a nitrogen overnight and
then partitioned between Et20 and 0.1 N HC1. The organic phase was
concentrated in vacuo, and the residue obtained purified on a silica gel column
eluting with 4% isopropanol in methylene chloride to give 159 mg of the title
20 compound, m.p. 111-116 °C. MS (FAB) m/z: M+K= 1048.
Example 40
Formula VII: Ri-= methyl: R2^= R 9 _= H. R^= OH. R4 and R£ taken together are
oxo: R& and R2 taken together are oxo: X and Y taken together are oxo:
25 Rg _= QCH2C(Q N )NHPh
A solution of rapamycin (0.58 g, 0.63 mmol) in dichloromethane (10 mL)
containing rhodium(II)acetate dimer (3 mg) is refluxed while N-phenyl-
diazoacetamide (101 mg, 0.63 mmol) in dichloromethane (1 mL) is added
dropwise. After complete addition the reaction is refluxed for 30 minutes and
30 additional N-phenyl-diazoacetamide (202 mg, 1.26 mmol) in dichloromethane
(1.5 mL) is added dropwise with reflux continuing 30 minutes after complete
addition. The solvent is removed in vacuo and the residue purified by HPLC on
silica gel. Fractions containing desired product are pooled, and concentrated, to
constant weight under high vacuum to give the desired product .
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Example 41
Formula VII: Rl=methvl: R2=R2=H. R3=0H. Ri and R5 taken together are oxo:
R 6 and RZ taken together are oxo: X and Y taken together are oxo:
5 R &=OCH2C(OWCH2CH2 V7Q
A solution of rapamycin (0.58 g, 0.63 mmol) in dichloromethane (10 mL)
containing rhodium(II)acetate dimer (3 mg) is refluxed while morpholino-
diazoacetate (98 mg, 0.63 mmol) in dichloromethane (1 mL) is added dropwise.
After complete addition the reaction is refluxed for 30 minutes and additional
10 morpholino-diazoacetate (196 mg, 1.26 mmol) in dichloromethane (1.5 mL) is
added dropwise with reflux continuing 30 minutes after complete addition. The
solvent is removed in vacuo and the residue purified by HPLC on silica gel.
Fractions containing desired product are pooled, and concentrated, to constant
weight under high vacuum to give the desired product .
15
Example 42
Formula VII: R l = methyl: Ri =R2.= -H: R2 = -QH:
R i and R 5 - taken together = O: R£ and R2 taken together = O:
X and Y taken together = O: R& = -OCHoCfO^NH^-Cl-Ph)
20 A solution of rapamycin (0.58 g, 0.63 mmol) in dichloromethane (10 mL)
containing rhodium(II)acetate dimer (3 mg) is stirred at 0 °C while N-p-Cl-
phenyl diazoacetamide (101 mg, 0.63 mmol) in dichloromethane (1 mL) is added
dropwise (24 hours). After complete addition the reaction is maintained at 0 °C
for an additional 24 hours. The solvent is removed in vacuo and the residue
25 purified by chromatography on silica gel to provide the title compound.
Example 43
Formula VII: Rl= methyl: RZ =R2.= -H: Rl = -OH:
R 4 and R 5 - taken together = O: R& and Rl taken together = O:
30 X and Y taken together = O: RS = -OCH^O^NRM RZI.
where R2 1R25 . taken together is (CHoCHoV? 0 -
The title compound is prepared using the procedure described in Example
42 and substituting 4-(2-diazo-l-oxo-ethyl)-morpholine for N-phenyl
diazoacetamide.
-92-
Example 44
Formula VH: Rl= methvl: Rl =R2-= -H: R2 = -QH:
R 4 and RS taken together = O: R& and Rl taken together = O; X arid Y taken
together = O: R& = -OCHoCrO^NHCHoCHoCHoOCfCnCFh .
The title compound is prepared using theprocedure described in Example
42 and substituting N-(3-acetyloxypropyl)-diazoacetamide for N-phenyl
diazoacetamide.
Example 45
Formula VH: Rl= methvl: Rl =R2_= -H: Rl = -OH:
R 4 and R£ taken together = O: R£ and R l taken together = O:
X and Y taken together = O: R& = -OCHoCfQtNH^-pvridvD.
The title compound is prepared using theprocedure described in Example
42 and substituting N-(4-pyridyl)-diazoacetamide for N-phenyl diazoacetamide.
Example 46
Formula VH: Rl= methvl: Rl =R2_= -H: Rl = -OH:
R 4 and R5 taken together = O: R6 and Rl taken together = O:
X and Y taken together = O: R& = -OCHoCfO-lNHCHoCfOIOffluorenvlmethvll
The title compound is prepared using theprocedure described in Example
42 and substituting N-(2-(fluorenylmethyloxy)-2-oxo-ethyl)-diazoacetamide for
N-phenyl diazoacetamide.
Example 47
Formula VII: Rl= methvl: Rl =R2 _= -H: R2 = -OH:
R4 and R5 . taken together = O: R6 and Rl taken together = O:
X and Y taken together = O: R& = -OCHoCfO^NHCHoCCOIOH
The compound resulting from Example 46 is dissolved in
dichloromethane and treated with 1 equivalent of piperidine. After complete
consumption of starting material, as evidenced by TLC, the material is purified
by chromatography on silica gel to provide the title compound.
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Example 48
Formula VII: Rl = methyl: R2 = -H: Rl = -OH: R4 and R S taken together = Q:
R6 and R l taken together = O: X and Y taken together = O:
5 RS = -OCr= OVNf2'-nvridvlmethvnfN.N-dimethvlarninor)ronvn: RS . = -H
The title compound is prepared from the compound resulting from
Example 2 and N-(2'-pyridylmethyl),N-(N,N-dimethylaniinopropyl)arnine
according to the procedure described in Example 3.
10 Example 49
Formula VII: Ri= methyl: R2 = -H: R l = -OH: Ri and R 5 taken together = O:
R£ and Rl taken together = O: X and Y taken together = O:
R& = -OCr=OVNrph envn-rN.N-dimethvlaminopronvn: R 9 - -H
The title compound is prepared from the compound resulting from
15 Example 2 and N-(phenyl)-N-(N,N-dimethylaminopropyl)arnine according to the
procedure described in Example 3.
Example 50
Formula I: Rl= methyl: Rl = H: R l = OH: Rl and Ri taken together = O-
20 R£ and R l taken together = O: X and Y taken together = O: RS = H- Rg = Nj-
RlQ a = QCH 2 : RM^H
To a solution of the compound resulting from Example 13 (937.2 mg,
1.02 mmol) in 5 mL of acetone was added sodium azide (355.6 mg, 5.47 mmol)
in 0.5 mL of water. The reaction mixture was stirred overnight at room
25 temperature. Additional water (1 mL) was added, and the reaction mixture was
stirred at room temperature for an additional 1 day. Anhydrous sodium sulfate (2
g) was added and stirring was continued for 30 minutes. The crude mixture was
then passed through a silica gel column. This partially purified material was
rechromatographed on silica gel eluting with 35% acetone in hexane to obtain
30 the title compound (380 mg, 40%) which was recrystallized from ether, m.p.
141-146 °C (dec). MS (FAB) mlz: M + K = 977.
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Example 5 1
Formula III: Rl= methvl: R2 = H: Rl = OH: R4 and R5 taken together = O:
R 6 and Rl taken together = O: X and Y taken together = O: R& = H: RS = NH7:
5 RlQ a = QCH^ : R^b = H
To a solution of the compound resulting from Example 50 (100 mg,
0.107 mmol) in 1 mL of THF containing 0.2 mL of water was added
triphenylphosphine (0.25 g, 0.954 mmol). The reaction mixture was stirred at
room temperature for 3 days and then concentrated in vacuo. The residue was
10 partitioned between Et20 and water. The organic phase was dried over
magnesium sulfate, concentrated in vacuo and purified by silica gel
chromatography to afford the title compound. MS (FAB) mlz: M+K= 951.
Example 52
15 Formula III: Rl= methvl: R2 = H: R.2. = OH: R4 and R5 taken together = O:
R 6 and Rl taken together = O: X and Y taken together = O; R£ = H: R2 = NHAc:
Rlfl a - QCH r. RlX&> = H
Acetic anhydride (0.15 mL) is added into a solution of the compound
resulting from Example 51 (1 g) in dichloromethane (5 mL) followed by N-
20 methylmorpholine (0.5 mL) at 0 °C. After stirring at that temperature for 30
minutes, the reaction mixture is partitioned bewteen ether and 0.1N hydrochloric
acid. The organic phase is washed once with brine, dried over magnesium
sulfate and the solvent removed in vacuo. The crude product is purified by silica
gel chromatography eluting with 50% acetone in hexanes.
25
Example 53
Formula III: R l = methvl: R2 = H: R3 = OH: Ri and Ri taken together = O:
R fi and Rl taken together = O: X and Y taken together = O: R& = H: Ri = NCO:
RlQ a = QCH^ : RiOb = H
30 A solution of triphosgene (0.15 g) in 2 mL dry dichloromethane is added
into a stirred solution of the compound resulting from Example 51 (1 g) in
pyridine (10 mL) at 0 °C. After being stirred at that temperature for 3 hours, the
reaction is partitioned between ether and 0.1 N hydrochloric acid. The organic
phase is washed once with brine, dried over magnesium sulfate and solvent
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removed in vacuo. The product is purified by silica gel chromatography eluting
with 50% acetone in hexanes.
Example 54
5 Formula III: Rl= methvl: R2 = H: R2 = OH: R l and Rl taken together = O-
RA_and R l taken together = O: X and Y taken together = O: R& = H:
R £ = NHSCbPh: Rl fl a = QCFh : RlQh = H
The title compound is prepared from the compound resulting from
Example 52, benzenesulfonyl chloride and N-rnethylmorpholine in
10 dichloromethane according to the procedure described in Example 52.
Example 55
Formula IIT: Rl= methyl; R2=J3iR3__=_OHlR1 and R 5 taken together = Or
R£ and Rl taken togeth er = O: X and Y taken together = O: R& = H:
15 R £ = NHCrO)NHPh: Rl fi a = QQUr : RlSh = H
Phenyl isocyanate (0.15 mL) is added into a solution of the compound
resulting from Example 51 (1 g) in tetrahydrofuran (5 mL) followed by N-
methylmorpholine (0.3 mL) at 50 °C. After being stirred at that temperature for
30 minutes, the reaction mixture is partitioned bewteen ether and 0.1 N
20 hydrochloric acid. The organic phase is washed once with brine, dried over
magnesium sulfate and solvent removed in vacuo. The crude product is purified
by silica gel chromatography eluting with 50% acetone in hexanes.
Example 56
25 Formula III: Rl= methyl; R2fjHLR2=_QHLR4 and R 5 taken together = O-
R£ and Rl taken toget her = O: X and Y taken together = O; RS = H:
R9 = NHCf=0)NH-NMe 2 : Kl Oa = OPH^ IQh^H
1,1-Dimethylhydrazine (0.07 g) is added into a solution of the compound
resulting from Example 54 (1 g) in pyridine (5 mL) at 0 °C and refregirated
30 overnight. Pyridine is removed in vacuo, and the crude mixture is purified by
silica gel chromatography eluting with 65% acetone in hexanes.
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Example 57
Formula II: Rl= methvl: R 2 - = H: Rl = OH: Rl and R£ taken together = O: R£
and R Z taken together = O: X and Y taken together = O: R& = H: R2 = Se-Ph:
Rlfl a = QCH^ : RlQk = H
5 Benzeneselenol (0.2 mL) is added into a stirred solution of the tide
compoud of Example 1 (1 g) and diisopropylethylamine (0.2 mL) in dry
tetrahydrofuran (5 mL) at 0 °C. After being stirred at that temperature for 2
hours, the reaction mixture is partitioned between ether and' 0.1 N hydrochloric
acid. The organic phase is washed once with brine, dried over magnesium
10 sulfate and solvent removed in vacuo. The product is purified by silica gel
chromatography eluting with 40% acetone in hexanes.
Example 58
Formula II: Rl= methvl: R 2 - = H: R3. = OH: Ri and R5 taken together = O: R6
15 and Rl taken together = O: X and Y taken together = O; Rl = H: Ri = SeCOVPh:
Rlfl a = QCH r. = H
3-Chloroperoxybenzoic acid (50-60%, 0.5 g) is added into a stirred
suspension of the compound resulting from Example 56 (1 g) and powdered
cesium carbonate (1 g) in dichloromethane (10 mL) at 0 °C. After being stirred
20 at that temperature for 1 hour, the reaction mixture is partitioned between ethyl
acetate and 0.1 N sodium bicarbonate. The organic phase is washed once with
brine, dried over magnesium sulfate and solvent removed in vacuo. The product
is purified by silica gel chromatography eluting with 50% acetone in hexanes.
25 Example 59
Formula IVb: Rl= methvl: R 2 - = H: R3 = OH: R4 and R 5 - taken together = O:
R6 and Rl taken together = O: X and Y taken together = O: Ri £ a = QCH^ :
RlOfa = H: R& = RiS = OH. R£ = Rl £ = H
N-Methylmorpholine N-oxide (0.26 g) is added into a stirred mixture of
30 the compound resulting from Example 37 (0.9 g) and osmium tetroxide (0.03
mL, 4% solution in water) in tetrahydrofuran (20 mL) at room temperature for 7
days. The reaction mixture is partitioned between ether and 1 N sodium
hydrogen sulfite. The organic phase is washed once with brine, dried over
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magnesium sulfate and the solvent removed in vacuo. The product is purified by
silica gel chromatography eluting with 50% acetone in hexanes.
Example 60
5 Formula TVh: Rl = methyl: Rl = H: R l = OH: Rl and R l taken together = O:
R.6 and R l taken together = O: X and Y taken together = O; Rl fl a = QCH ?:
Rl^^^H^^R IS^h l r2 and R 19 taken together fnrrn a cvclic carhnr , atP
A solution of triphosgene (0.15 g) in 2 mL dry dichloromethane is added
into a stirred solution of the compound resulting from Example 58 (1 g) in
10 pyridine (10 mL) at 0 °C. After stirring at that temperature for 3 hours, the
reaction is partitioned between ether and 0. 1 N hydrochloric acid. The organic
phase is washed once with brine, dried over magnesium sulfate and the solvent
removed in vacuo. The product is purified by silica gel chromatography eluting
with 50% acetone in hexanes.
15
Example 61
Formula IVb: Rl= methyl: R2 = H; Rl = OH: Rl and R l taken together = O- R6
and R2 taken together = O; X and Y taken together = O: Rl Q a = OCHy RlQb =
H: RS = Rig = H:
20 R- and RI 2 taken together form a cvclic sulfate
The title compound is prepared from the compound resulting from
Example 58 and sulfuryl chloride in pyridine according to the procedure
described in Example 59.
25
Example 62
Formula IVb: Rl= methvl: R2_= H: Rl = OH: Rl and R l taken together = Or
R6 and Rl taken togeth er = O: X and Y taken together - O; Rl fi a = QCH^ :
E^^JHi^WEl&^JiLRaand Rl 2 taken together form a ryclic sulfite
30 The title compound is prepared from the compound resulting from
Example 58 and thionyl chloride in pyridine according to the procedure
described in Example 59.
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Example 63
Formula II: Rl= methvl: R.2. = H: R3. = OH: Ri and R5 taken together = O: R6
and Rl taken together = O: X and Y taken together = O: R& = H:
R 2 = -SCr=NmNH 2 : R^ = QCH? : Rlflb = H.
5 Powdered thiourea (0. 106 g) was added into a stirred solution of the
compound resulting from Example 13 (0.94 g) and 2,6-lutidine (0.3 raL) at
-78 °C and allowed to warm up to room temperature. After stirring at room
temperature for 16 hours, the solvent was removed in vacuo, and the product was
used in next step without further purification.
10
Example 64
Formula II: Rl= methvl: R2 = H: R3 - = OH: Ri and Ri taken together = Q: R£
and R l taken together = O: X and Y taken together = O: R& = H: Rg = SH:
RlQ a = QCH r R-U& = H
15 The compound resulting from Example 63 was added 85 (4.L (1
equivalent) of morpholine at room temperature. After stirring for two hours, an
additional 20 (J.L of morpholine was added and stirring was continued for an
additional hour. An additional aliquot of morpholine (60 (J.L) was added and
stirring was continued for an additional 30 minutes. The reaction mixture was
20 partitioned between ethyl acetate and water. The organic phase was dried over
magnesium sulfate and concentrated in vacuo. The residue was purified by silica
gel chromatography to give the title compound (189 mg). m.p. 105-1 1 1 °C. MS
(FAB) mlz: M + K = 968.
25 Example 65
Formula II: Rl= methvl: Rl = H: R3 = QH: Ri and R i taken together = O: R£
and R 2 taken together = O: X and Y taken together = O: R& = H:
R9 = -SCr=NNH 2 WHo: Rl fla = QCH^ TiMl = H
Powdered thiosemicarbazide (0.106 g) is added into a stirred solution of
30 the compound resulting from Example 13 (0.94 g) and 2,6-lutidine (0.3 mL) at
-78 °C and allowed to warm to room temperature. After stirring at room
temperature for 16 hours, the solvent is removed in vacuo, and the product is
purified by silica gel chromatogrphy eluting with 5 % isopropanol in
dichloromethane.
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Example 66
Formula II: R l= methvl: R2 = H: R l = OH: Rl and R5 taken together = O: R6
and R 2 taken together = O: X and Y taken together = O: R& = H: R2 =
5 -SCH 2 C0 2 Et: Rl fl a = QCH^: R^ = H
Ethyl bromoacetate (0.2 mL) is added into a stirred solution of the
compound resulting from Example 64 (1 g) and 2,6-lutidine (0.2 g) in
acetonitrile under nitrogen at room temperature. After stirring at room
temperature for 5 hours, the solvent is removed in vacuo, and the product is
10 purified by silica gel chromatography eluting with 40% acetone in hexanes.
Example 67
Formula II: Rl= methvl: Rl - H: R3. - OH: Rl and Rl taken together = O: R 6
and R l taken together = O: X and Y taken together = O: R& = H:
!5 R 2 - 4'-PvridvlCH2S-: Rl fl a = QCHg : RlQh. = H
The title compound is prepared from the compound resulting from
Example 64, 4-picolyl chloride hydrochloride and 2,6-lutidine in acetonitrile at
60 °C according to the procedure described in Example 66.
Example 68
Formula II: Rl= methvl: Rl = H: R l = OH: Rl and R i taken together = O: Rfi
and Rl taken together = O: X and Y taken together = O: R& = H:
R 2 = 3'-PvridvlCH2S-: Rl fl a = QCH 2 : Rl£h = H
The title compound is prepared from the compound resulting from
Example 64, 3-picolyl chloride hydrochloride and 2,6-lutidine in acetonitrile at
60 °C according to the procedure described in Example 66.
Example 69
Formula IT: Rl= methvl: Rl = H: Rl = OH: Rl and R i taken together = O; R 6
and R l taken together = O: X and Y taken together = O: R£ = H:
R9 = 2 , -Pvridv1CH 2 S-- Rl Oa = nrH 2 -_R J0b_=H
The title compound is prepared from the compound resulting from
Example 64, 2-picolyl chloride hydrochloride and 2,6-lutidine in acetonitrile at
60 °C according to the procedure described in Example 66.
20
25
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Example 70
Formula II: Rl= methyl: R2 = H: R2 = OH: Rl and R5 taken together = O: R6
and Rl taken together = O: X and Y taken together = O: R& = H:
5 R 2 = -SCHoCOCCbEt: Rlfla = QCH^ : R^& = H
The title compound is prepared from the compound resulting from
Example 64, ethyl bromopyruvate and 2,6-lutidine in acetonitrile at 60 °C
according to the procedure described in Example 66.
10 Example 71
Formula HE: Rl= methvl: R 2 - = H: R2 = QH: R4 and RS taken together = O:
R £ and Rl taken together = O: X and Y taken together = O: R& = H:
R 2 = -(pvridin-4-on-l-vl): Rl fl a = QCH^ : RlQh = H
To a solution of the compound resulting from Example 13 (1.01 mmol)
15 and 2,6-lutidine (0.2 mL) in methylene chloride (2 raL) was added 4-
hydroxypyridine (0.5132 g) in 2 mL of THF containing 0.5 mL of methanol.
The reaction mixture was stirred at room temperature for 36 hours and then
chromatographed on silica gel eluting with 50% acetone in hexanes to afford
0.277 g of the title compound, m.p. 126-131 °C. MS (FAB) m/z: M + K = 1029.
20
Example 72
Formula III: Rl= methvl: R2 = H: Rl = OH: R4 and R $ taken together = O:
R& and R l taken together = O: X and Y taken together - O: R& = H:
R9 - -(pvridin-2-on-l-vn: Ri Q a = QCH^ : R^ = H
25 To a solution of the compound resulting from Example 13 (924 mg, 0.88
mmol) in 5 mL of THF was added 0.25 mL of 2,6-lutidine followed by 51 1.2 g
of 2-hydroxypyridine (0.51 12 g) in dichloromethane-tetrahydrofuran (1:1,4
mL). The reaction mixture was stirred at room temperature overnight and then
chromatographed on silica gel eluting with 50% acetone in hexanes to afford
30 0.45 g of the title compound, m.p. 101-106 °C. MS (FAB) m/z: M + K = 1029.
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Examnle 73:
Formula III: Rl= methvl: R 2 - = H: R2 = OH: R4 and R 5 taken together = O:
R6 and R 2 taken together = O: X and Y taken together = O: R& = H:
R 2 = the ethylene ketal of nvridin-4-on-lvl: Rl fl a = QCH^: Rl i& = H
5 A suspension of 4-(hydroxethoxy)pyridine (0.5 1 g) in 1 : 1
dichloromethane-tetrahydrofuran (4 mL) is added into a stirred solution of the
compound resulting from Example 13 (0.95 g) and 2,6-lutidine (0.2 mL) in dry
tetrahydrofuran at room temperature. After stirring at room temperature for 36
hours, the reaction mixture is chromatographed on silica gel eluting with 50%
10 acetone in hexanes to afford the title compound.
Example 74
Formula I: R l= methvl: RZ = H: Rl = OH: Rl and R 5 taken together - O:
R£ and R l taken together = O: X and Y taken together = O: R& = H: RS . = OCH^ :
15 Rifl a = QCH 2 : Rl0b = H
To a solution of the compound resulting from Example 13 (1.21 g, 1.11
mmol) in 5 mL of THF was added 0.25 mL of 2,6-lutidine followed by 0.87 g
(6.26 mmol) of 4-(2-hydroxyethyl)pyridine and 0.5 mL of methanol. The
reaction mixture was stirred at room temperature under nitrogen overnight and
20 then poured onto a silica gel column and eluted with 35% acetone in hexanes to
give partially purified material. This material was rechromatographed on silica
gel eluting with 25% acetone in hexanes to afford 462 mg. This material was
rechromatographed on silica gel eluting with 1:1 ethyl acetate-hexane to afford
108 mg of pure title compound, m.p. 102-106 °C. MS (FAB) m/z: M + K = 966.
25
Example 75
Formula VII: R L= methvl: R2 =H:R l= OH: Ri and R i taken together = O:
R& and R l taken together = O: X and Y taken together = O: R& = OCHoSCH ^:
R9 = H: Ri O a - QCHr . Rlflh = H
30 To a solution of rapamycin (1.0349 g) in DMSO (3 mL) was added acetic
anydride (3 mL) and 0.5 mL methylene chloride. The reaction mixture was
stirred one day at room temperature and then partitioned between ether and
water. The organic phase was dried over magnesium sulfate and concentrated in
vacuo. The residue was purified by silica gel column chromatography eluting
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with 25% acetone in hexanes to afford partially purified compound which was
rechromatographed on silica gel eluting with 2% isopropanol in methylene
chloride to give pure title compound (270.7 mg). m.p. 94-98 °C. MS (FAB)
mlz: M + K = 1012.
5
Example 76
Formula I: Rl= methvl: R 2 - = H: R 3 - = OH: Ri and R5 taken together = O:
R£ and R 2 taken together = O: X and Y taken together = O: R& = H;
R S = OCEbSCH? : R-1 & = OCH^ : R ^ = -H
10 The compound resulting from Example 1 (1 g) is dissolved in anhydrous
dimethyl sulfoxide (1.5 mL), and the mixture is stirred at room temperature for
14 hours. The reaction mixture is partitioned between ether and water. The
organic phase is washed once with brine, dried over magnesium sulfate and
solvent removed in vacuo. The product is purified by silica gel chromatography
15 eluting with 40% acetone in hexanes.
Example 77
Formula VII: R l = methvl: R2 = H: R2. = OH: Rl and R l taken together = O:
R£ and R l taken together = O; X and Y taken together = O: R& = OH: R2 = H:
20 Rlfl a = -Q-n-Butvl: Rl Q h = -H
Toluenesulfonic acid (0.256 g) was added to a stirred solution of
rapamycin (1.13 g) in a solution of methylene chloride (20 mL) and n-butanol
(20 mL) at 0 °C. After stirring at 0 °C for 2 hours, the reaction mixture was
stirred at room temperature overnight. It was partitioned between ether and
25 water. The organic phase was washed once with brine, dried over magnesium
sulfate and solvent removed in vacuo. The product was purified by silica gel
chromatography eluting with 40% acetone in hexanes to afford 0.41 g of the title
compound. MS (FAB) mlz: M + K = 994.
30
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Example 78
Formula I: Rl= methvl: R2 = H: R3. = OH: Ri and R5 taken together = O:
R6 and R l taken together = O: X and Y taken together = O: R& = H: R 2 = OH:
Rlfl a = -Q-n-Butvl: Rl Qh = H
5 The title compound is prepared from the compound resulting from
Example 10, n-butanol and toluenesulfonic acid according to the procedure
described in Example 77.
Example 79
10 Formula I: R l= methvl: R2 - = H: R3 - = OH: Rl and R5 taken together = O:
R6 and R l taken together = O: X and Y taken together = O: R& = H: RS = QH:
Rlfl a = -H: Rl Q b = QCH^
The title compound is prepared from the compound resulting from
Example 10, methanol and toluenesulfonic acid according to the procedure
15 described in Example 77.
Example 80
Formula I: R l= methvl: R2 = R:Rl = QH: Rl and Rl taken together -- O:
R£ and R l taken together = O: X and Y taken together = O: R& = H: Rg = OH:
20 Rifl a = -H: Rl Q h = h.
Triethylsilane (0.2 g) is added to a stirred solution of the compound
resulting from Example 10 (1 g) and trifluoroacetic acid (1.2 g) in
dichloromethane at -45 °C. After being stirred at that temperature for 1 hour, the
reaction mixture is partitioned between ether and sodium bicarbonate. The
25 organic phase is washed once with brine, dried over magnesium sulfate and
solvent removed in vacuo. The product is purified by silica gel chromatography
eluting with 40% acetone in hexanes.
30
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Exarrrple 8 1
Formula I: Rl= methvl: R2 = H: R3. = OH: R± and R5 taken together = O:
R & and R2 taken together = O: X and Y taken together = O: R& = H:
R S = OH: Rl fl a = - Allvl: Rl Qk = H
5 The title compound is prepared from the compound resulting from
Example 10, allytrimethylsilane and trifluoroacetic acid according to the
procedure described in Example 77.
Example 82
10 Formula I: R l= methvl: R2 = H: Rl = OH: Ri and R5 - taken together = O:
R6 and R l taken together = O: X and Y taken together = O: R& = H: R2 = QH:
Ri£ a an( j R lfl h taken together = O
A solution of the compound resulting from Example 10 (1 g) and DDQ (2
equivalent) is stirred in wet dichloromethane at room temperature overnight
15 The product is purified by silica gel chromatography eluting with 40% acetone in
hexanes.
Example 83
Alternate Preparation of
20 Formula IVb: Ri= methvl: R2 = H: R $ = OH: R4 and R5 taken together = O:
R& and R l taken together = O: X and Y taken together = O: Rl Q a = QCH^ :
E Jffl l=HLE& = R^.^H, RS and Rl £ taken together form a bond
A solution of the compound resulting from Example 58 (1 g) in
chloroform is stirred at 50-60 °C for 4 hours. The product is purified by silica
25 gel chromatography eluting with 40% acetone in hexanes.
Example 84
Formula I: Rl= methvl: Rl = H: R l = OH: Rl and R5. taken together = O:
R£ and R l taken together = O: X and Y taken together = Q; R& = H:
30 R 2 = -o-crovrH 2 :
The compound resulting from Example 1 is treated with acetic acid and
Hiinig's base in methylene chloride to afford the title compound.
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Example 85
Formula x . Rl= methvl: Rl = H: R 3 . = OH: Rl and R5 taken together = O:
R 6 and Rl taken together = O: X and Y taken together = O: R& = H:
R 2=-Q-CrOVr)henv1:
5 The compound resulting from Example 1 is treated with benzoic acid and
Hiinig's base in methylene chloride to afford the title compound.
Example 86
Formula I: R l= methvl: R 2 - = H: R3- = OH: Ri and R 5 taken together = O:
10 R6 and R 2 taken together = O: X and Y taken together = O: R& = H:
R 2 = -Q-CrOVr4-Dvridv1V.
The compound resulting from Example 1 is treated with isonicotinic acid
and Hiinig's base in methylene chloride to afford the title compound.
15 Example 87
Formula I: R l= methvl: RZ = H: R3. = OH: Rl and R5 taken together - O:
R6 and R l taken together = Q: X and Y taken together = O: RS = H;
R 2 = -Q-C(OVNfOCHVifCH V):
The title compound is prepared from the compound resulting from
20 Example 1 1 and N,0-dimethylhydroxylamine according to the procedures
described in Example 3.
Example 88
Formula ITT: R l= methvl: R2 = H: R 3 - = QH: Rl and R5- taken together = O:
25 R6 and R l taken together = O: X and Y taken together = O: R& = H:
R £=-NH-CfOVnhRnv1:
The title compound is prepared from the compound resulting from
Example 51 and benzoyl chloride in the presence of N-methylmorpholine in
dichloromethane according to the procedure described in Example 52.
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Example 89
Formula III: Rl= methyl: R.2 = H: R3. = OH: R.A and R5- taken together = O:
R 6 and Rl taken together = O: X and Y taken together = O: R& = H:
r £ = -NH-CfOVCHo-COoH:
5 The title compound is prepared from the compound resulting from
Example 51 and malonyl chloride in the presence of N-methylmorpholine in
dichloromethane according to the procedure described in Example 52.
Example 90
10 Formula III: Rl= methyl: R2 = H: R2 = OH: R4 and Rl taken together = O:
R 6 and Rl taken together = O: X and Y taken together = O: R& = H:
R9 = -NH-CfOVf CH 2 V>-C(>>H:
The title compound is prepared from the compound resulting from
Example 5 1 and succinic anhydride in the presence of N-methylmorpholine in
15 dichloromethane according to the procedure described in Example 52.
Example 91
Formula III: Rl= methyl: R2 = H: R2 = OH: R4 and R5 taken together = O:
R& and R l taken together = O: X and Y taken together = O: R& = H:
20 R 2 = -NH-CfOWCHoVCO oH:
The title compound is prepared from the compound resulting from
Example 51 and glutaric anhydride in the presence of N-methylmorpholine in
dichloromethane according to the procedure described in Example 52.
25 Example 92
Formula III: Rl= methyl: R 2 = H: R 2 = OH: R4 and R.2 . taken together = O:
R 6 and Rl taken together = O: X and Y taken together = O: R£ = H:
R 2 = -NH-CCOVrCHoVCOoH:
The title compound is prepared from the compound resulting from
30 Example 5 1 and adipoyl chloride in the presence of N-methylmorpholine in
dichloromethane according to the procedure described in Example 52.
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Example 93
Formula III: Rl= methvl: R2 = H: R3- = OH: R4 and Rl taken together = O:
R 6 and Rl taken together = O: X and Y taken together = O: R& = H:
R 2 _ ethylene ketal of pvridin-2-on-l-vl:
5 The title compound is prepared from the compound resulting from
Example 1 and 2-(2'-hydroxyethoxy)pyridine in the presence of N-
methylmorpholine in dichloromethane according to the procedure described in
Example 72.
10 Example 94
Formula 111: R l= methvl: R2 = H: Rl = OH: R4 and Rl taken together = O:
R& and R l taken together = O: X and Y taken together = O: R& = H:
R 2 = ethylene ketal of piperidin-4-on-l-vl
The title compound is prepared from the compound resulting from
15 Example 1 and the ethylene ketal of piperidin-4-one in the presence of N-
methylmorpholine in dichloromethane according to the procedure described in
Example 72.
Example 95
20 Formula III: R l= methvl: R2 = H: R3 - = OH: R4 and R l taken together = O:
Rfi and R l taken together = O: X and Y taken together = O: R& = H:
r 2 = -Cr)iperidin-4-ol-l-vn
The title compound is prepared from the compound resulting from
Example 1 and 4-hydroxypiperidine in the presence of N-methylmorpholine in
25 dichloromethane according to the procedure described in Example 72.
Example 96
Formula in: Rl= methvl: R2 = H: R2 = QH: R4 and Ri taken together = O:
R6 and R l taken together = O: X and Y taken together = O: R& = H:
30 R 2 = -(piperidin-4-on-l-vl)
The title compound is prepared from the compound resulting from
Example 1 and piperidin-4-one in the presence of N-methylmorpholine in
dichloromethane according to the procedure described in Example 72.
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Example 97
Formula III: Rl= methyl: R2 = H: Rl = OH: Rl and Rj. taken together = O:
R 6 and Rl taken together = O: X and Y taken together = O: R& = H:
r 2= -(piperidin-2-on-l-vD
5 The title compound is prepared from the compound resulting from
Example 72 by catalytic hydrogenation in ethanol using a palladium on carbon
catalyst
Example 98
10 Formula VII: Rl=CHq: R2=R 2=H: R2=0H: Rl and R5 taken together=Q:
R £ and Rl taken together=Q: X and Y taken together=Q;
R &= -OCHoCfCnOCoFU
A solution of rapamycin (304 mg, 0.33 mmol) and ethyl iodoacetate (276
liL, 2.33 mmol) in acetbnitrile (300 JJ.L) at 0 °C was treated with Ag20 (308 mg,
15 1.33 mmol) in small portions over 5 minutes. The reaction was then warmed to
ambient temperature and stirred for 5 days. The mixture was adsorbed onto
silica gel by dilution of the mixture with CH2CI2 (5 mL) followed by addition of
silica gel (70-230 mesh, 60 A, 5mL) and solvent evaporation. The adsorbed
silica bed was placed on a fresh pad of silica and eluted with mixtures of
20 CH2Cl2:CH3CN (9:1, 4:1, 2:1, 1:1). Fractions containing product were pooled,
concentrated and further purified by HPLC on YMC 15 micron spherical 60A
silica, eluting with a mixture of 3:1 hexane:acetone to provide desired product
(112 mg). MS (FAB) mlz: M+K = 1038. Anal, calc'd. for C55H85NO15: C,
66.04; H, 8.56; N, 1.40. Found: C, 65.83; H, 8.51; N, 1.36.
25
Example 99
Formula VII: R - ^CFn: r2=r9 = h : r3=QH: Rl and R5 taken together=Q: R6 and
R l taken together-O: X and Y taken together=Q:
R &= -OCHoCfOIOCHoPh^-OMe^
30 The title compound is prepared using the procedure of Example 98
substituting p-methoxy- benzyl iodoacetate for ethyl iodoacetate.
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Example 100
Formula VII: Rl=CH r. R2=R 2=H: R2=QH: Rl and R l taken together=Q:
R 6 and Rl taken together=Q: X and Y taken together=Q: R&= -OCHoCfO^OH .
The resultant product of Example 99 is treated with
5 dichlorodicyanobenzoquinone in warm benzene. The mixture is concentrated
and purified by chromatography on silica gel to provide pure title compound.
Example 101
Formula VII: R l=CHr. R2=r2=H: R3=QH: Rl and R l taken together=Q: R6 and
10 R l taken together=Q: X and Y taken together=Q: R&= -OCH2CfO)NRM R25 :
R24 = qch 2 : R25 = benzvl
The resultant product of Example 100 (912 mg, 0.94 mmol) is dissolved
in THF (3 mL) and cooled to 0 °C before adding N-methylmorpholine (103.4
|J.L, 0.94 mmol) followed by isobutyl chloroformate (122.2 \iL, 0.94 mmol). The
15 resulting suspension is stirred for 20 minutes at 0 °C after which time
N-benzyl,0-methyl-hydroxylamine (257 mg, 1.88 mmol) is added, and stirring is
continued overnight. The reaction mixture is purified by chromatography on
silica gel to provide the title compound.
20
Example 102
Formula VII: R l=CHr. R2=R9 =H: r2 =QH: R± and R l taken together=Q:
R £ and Rl taken together=Q: X and Y taken together=Q:
R &= -OCH 2 aCnNR2 4R25 : R24- CHl . R25 ^Q. benzvl
25 The title compound is prepared using the procedure of Example 101 and
substituting N-methyl-O-benzyl-hydroxylamine for N-benzyl-O-methyl-
hydroxylamine.
Example 103
30 Formula VII: R l^CFh: R^R ^H; r 2=QH; Rl and R l taken together=Q:
R6 and R l taken together=Q: X and Y taken together=Q:
R8 = -OCHoCrO^NHOCH^
The title compound is prepared using the procedure of Example 101 and
substituting O-methyl-hydroxylamine for N-benzyl-O-methyl-hydroxylamine.
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Example 104
Formula VII: Rl=CH;r . r 2=rS=H: R2=0H: RA and Rl taken together=Q: R6 and
R l taken together=Q: X and Y taken together=Q: R&= -OCHoCffflNRM RZi;
5 R24 =QC% ; R25 =CH^
The title compound is prepared using the procedure of Example 101 and
substituting N-methyl-O-methyl-hydroxylamine for N-benzyl-O-methyl-
hydroxylamine.
10 Example 105
Formula VII: Rl=CH r. R2=R 2=H: R3=OH: RA and R-S taken together=Q:
R 6 and Rl taken together=Q: X and Y taken together=Q:
R &= -OCH 2 C(CnNR2 4R25_; R24 =H: R25= C vclopropvl
The title compound is prepared using the procedure of Example 101 and
15 substituting cyclopropylamine for N-benzyl-O-methyl-hydroxylamine.
Example 106
Formula VII: R l =CH; v. R2=R 2=H: R2=OH: Rl and Rl taken together=Q:
R 6 and R2 taken together=Q: X and Y taken together=Q:
20 RS= -OCH2CfO)NR2 4R2S : R ^cch^ - R25 ^ cvc i opr0 p V i
The title compound is prepared using the procedure of Example 101 and
substituting N-cyclopropyl-O-methyl-hydroxylamine for N-benzyl-O-methyl-
hydroxylamine.
25 Example 107
Formula VII: R l =CH2 : R 2=R2=H: R3=QH: Ri and Rl taken together=Q:
R & and R2 taken together=Q: X and Y taken together=Q:
R &= -OCH2C(CnNR2 lR25_ : R24 =QCHr . R2 5=cvclohexvl
The title compound is prepared using the procedure of Example 101 and
30 substituting N-cyclohexyl-O-methyl-hydroxylamine for N-benzyl-O-methyl-
hydroxylamine.
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Example 108
Formula VTT: R i^rFh. R2^2=^%gH^la^ljaken together=Q:
R6 and R l taken together=Q: X and Y taken together=Q:
R 8= -OCH2CrO^NR2 4R2S; RM^QCHv R 25 = -CHoCHoOH.
The title compound is prepared using the procedure of Example 101 and
substituting N-(2-hydroxyethyl)-0-methyl-hydroxyIamine for N-benzyl-O-
methyl-hydroxylamine.
Example 109
10 Formula VII: R%CH 3 iR%R%HlR^OH; R4 and R l taken together=Q:
R6 and Rl taken together= Q: X and Y taken tope.ther=Q;
RS= -OCH 2 CrO->NR24R2j : R 24= H: R 25 = -CHoCOoCH 2 Phr4-OM^
The title compound is prepared using the procedure of Example 101 and
substituting glycine p-methoxybenzyl ester for N-benzyl-O-methyl-
15 hydroxylamine.
Example 110
Formula VII: R%CH 3 iR2^%H l r3=qh l r4 _ an d R l taken together=Q:
R6 and Rl taken togethe,r=Q- X and Y taken together=Q:
20 R &= -OCH 2 CrOWR2 4R2S : r^H; r2 5= -CH 2 C0 2 H
The title compound is prepared by the procedure described in Example
100 substituting the product from Example 109 for the product from Example
99.
25 Example 1 1 1
Formula VII: R%CH3^R 2 ^E%HiR,3^QHlR1 and R l taken together=Q-
Rfi and RZ taken together =Q; X and Y taken toPe,the.r=r)-
RS= -OCH 2 CYCr>NR24R23 : r^H: R ^-biphenvlvl
The title compound is prepared using the procedure of Example 101 and
30 substituting 3-biphenylamine for N-benzyl-O-methyl-hydroxylamine.
-112-
Example 1 12
Formula VII: R i ^CH^ : R 2=R2=H: R2=0H: Rl and taken together=Q:
R & and RZ taken together=0; X and Y taken toeether=Q:
R £= -OCHoCCOtNRM R^; R ^-CHoCebOH: R2 5 = 3-biphenvlvl
The title compound is prepared using the procedure of Example 101 and
substituting N,N-(ethanol-2-yl)-(3-biphenyl)-amine for N-benzyl-O-methyl-
hydroxylamine.
Example 113
Formula VII: Rl^CKh : R2=R 2=H: R3=OH: Ri and R5 taken together=Q:
R & and taken together=Q; X and Y taken together=Q;
R S= -OCH2CrO^NR2 4R25. : R ^-C^C^NfCH^CPbC^OHV. R2 5 = phenyl
The title compound is prepared using the procedure of Example 101 and
substituting N-phenyl-N'-methyl-N'-(ethanol-2-yl)-ethyldiamine for N-benzyl-O-
methyl-hydroxylamine.
Example 114
Formula VII: Rl^Crt? : R2=R 2=H: R2=0H: Rl and R5. taken together=Q:
R & and Rl taken together=Q: X and Y taken together=Q:
RS = -0CH 2 C(0')NR^ R25; R24 = _CH2CH 2 NrCH2 )2: R ^= phenyl
The title compound is prepared using the procedure of Example 101 and
substituting N-phenyl-N',N'-dimethyl-ethyldiamine for N-benzyl-O-methyl-
hydroxylamine.
Example 115
Formula VII: R l ^CH^ R2=r 9=H; R2=0H: R4 and R 5 taken together=Q:
R & and taken together=Q: X and Y taken together=Q:
R8 = -OCH 2 CrO')NR2 4R2S; R ^CHore-pvridvD: R2 5 = CTfrG-pvridvD
The title compound is prepared using the procedure of Example 101 and
substituting substituting 3,3'-dipipicolylamine for N-benzyl-O-methyl-
hydroxylamine.
-113-
Example 1 16
Formula VII: R l =CHr . R2=R 2=H: R3=QH: R4 and R5 taken together=Q:
R & and Rl taken together=Q: X and Y taken together=Q:
R S= -OCHoCfOINH-^-morDholinvl')
The compound resulting from Example 100 is activated as in Example
101 and then treated with 1 equivalent of 4-aminomorpholine and 0. 1 equivalents
of 4-dimethylaminopyridine instead of N-benzyl-O-methyl-hydroxylamineto
give the title compound.
Example 1 17
Formula VII: Rl=CH 2 : R2=R 2=H: R2=0H: Ri and R$ taken together=Q:
R & and Rl taken together=Q: X and Y taken together=Q:
R &= -OCHoCCOtNRM Ra S; where R2A and taken together=
-CH2CH2SCH2CH?-, thus forming a six membered ring incorporating the
nitrogen to which thev are attached
The compound resulting from Example 100 is activated as in Example
101 and then treated with thiomorpholine instead of N-benzyl-O-methyl-
hydroxylamine to give the title compound.
Example 118
Formula VII: R i ^CH 2 : R2=R 2=H: R^OH: Rl and R-S taken together=Q:
R 6 and R2 taken together=Q: X and Y taken together=Q:
R S= -OCH2CrO)NR2 4R2S; r24 =H: R25= 4-CF2-phenvl
The compound resulting from Example 100 is activated as in Example
101 and then treated with 4-aminobenzotrifluoride instead of N-benzyl-O-
methyl-hydroxylamineto give the title compound.
Example 119
Formula VII: Rl=CH r. R2=R 2=H: R2=0H: Ri and R$ taken together=Q:
R fi and R2 taken together=Q: X and Y taken together=Q:
R £= -OCH2CrO)NR2 lR25 : r ^h- R2 5 =4. F . phenv i
The compound resulting from Example 100 is activated as in Example
101 and then treated with 4-fluoroaniline instead of N-benzyl-O-methyl-
hydroxylamine to give the title compound.
-114-
Example 120
Formula VII: Rl=CHg: R2=Rg=H: R3=0H: Rl and taken together=Q:
R & and Rl taken together=Q: X and Y taken together=Q:
R &= -OCH2CfO>NR2 lR2£ : R24= H : R2 2 = 4-f4-morpholinoVphenvl
The compound resulting from Example 100 is activated as in Example
101 and then treated with 4-morpholinoaniline instead of N- benzyl- O-methyl-
hydroxylamine to give the title compound.
Example 121
Formula VII: Rl=CH3 : R2=R2=H: R2=0H: RA and R5 taken together=Q:
R 6 and Rl taken together=Q: X and Y taken together=Q:
R &= -OCHoCCOINRM rZS; R24 =H: R21= 4-HO-phenvl
The compound resulting from Example 100 is activated as in Example
101 and then treated with p-aminophenol instead of N-benzyl-O-methyl-
hydroxylamine to give the title compound.
Example 122
Formula VII: R l =CHr , R 2=R2=H: R2=0H: Rl an d R5 taken together=Q:
R & and Rl taken together=Q: X and Y taken together=Q;
R S= -OCH 2 CCC»NR2 4r25 : r24 =H: R2 5 = 3-pvridvl
The compound resulting from Example 100 is activated as in Example
101 and then treated with 3-aminopyridine instead of N-benzyl-O-methyl-
hydroxylamine to give the title compound.
Example 123
Formula VII: Rl^CH^ : r2=r 2=H: R3=QH: RA and Ri taken together=Q:
R & and Rl taken together=Q: X and Y taken together=Q:
R &= -OCH 2 CrO')NR2 4R25 : r24 =H: R2 5 = 4-pvridvl
The compound resulting from Example 100 is activated as in Example
101 and then treated with 4-aminopyridine instead of N-benzyl,0-methyl-
hydroxylamine to give the title compound.
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Example 124
Formula VIT: R%CH3iR2=r2=HlR3=OH; Rl and R l taken together=Q:
R£ and R l taken together=Q: X and Y taken together=Q:
R &= -OCH 2 CfCnNR2 4R2£ : r^h- R 25= 2-pvridvl
The compound resulting from Example 100 is activated as in Example
101 and then treated with 2-aminopyridine instead of N-benzyl-O-methyl-
hydroxylamine to give the title compound.
Example 125
Formula VII: R-^CHsI^^^HlR^QHiRI and R j taken tog ether=Or
R6 and R l taken together=Q: X and Y taken toeether=Q:
R &= -OCH 2 CrO->NR2 4R2i : r24=H: R25 = NHCOoCFfo
The compound resulting from Example 100 is activated as in Example
101 and then treated with methylcarbazate instead of N- benzyl- O-methyl-
hydroxylamine to give the title compound.
Example 126
Formula VII: R%CH 3 iR2^%h 1 _r^OHl_R1 and R j taken togeth p,r = o-
R6 and Rl taken together =Q: X and Y taken togethf»x=Q-
R& = -QCHoCr OH L-prolinecarboxarnide')
The compound resulting from Example 100 is activated as in Example
101 and then treated with L-prolinecarboxamide instead of N-benzyl-O-methyl-
hydroxylamineto give the title compound.
Example 127
Formula VII: RisCHaLEfeB^HLR^QHLE^-and R $ taken together=Q:
R6 and Rl taken together =Q: X and Y taken topethfT=Q;
R &=-QCH9CrOyfD-proIinecarhnyarmHe)
The compound resulting from Example 100 is activated as in Example
30 101 and then treated with D-Prolinecarboxamide instead of N-benzyl-O-methyl-
hydroxylamineto give the title compound.
10
15
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Example 128
Formula VII: R l =CHj ,: R2=R g=H: R2=0H: Rl and RS taken together=Q:
R 6 and Rl taken together=Q; X and Y taken together=Q:
R&= -OCHoaOU L-prolinol").
5 The compound resulting from Example 100 is activated as in Example
101 and then treated with L-prolinol instead of N-benzyl-O-methyl-
hydroxylamineto give the title compound.
Example 129
10 Formula VII: Ri=CFh : R2=R g=H: R2=0H: Rl and R5 taken together=Q:
R 6 and Rl taken together=Q: X and Y taken together=Q:
RB = -OCHoCfOU D-T3rolinon
The compound resulting from Example 100 is activated as in Example
101 and then treated with D-prolinol instead of N-benzyl-O-methyl-
15 hydroxylamineto give the title compound.
Example 130
Formula VII: Rl =CHr. R2=R 2=H: R 3 =OH: Rl and R5 taken together=Q:
R 6 and Rl taken together=Q: X and Y taken together=Q:
20 R8 = -OCHoaO^NfCHoC^OH^NHfCOoCFh 't
The compound resulting from Example 100 is activated as in Example
101 and then treated with N-(ethanol-2-yl)-N'-carbomethoxy-hydrazine instead
of N-benzyl-O-methyl-hydroxylamine to give the title compound.
25 Example 131
Formula VII: R l=CH 2 : r2=r 2=H: R 3 =QH: Rl and R5 taken together=Q:
R & and Rl taken together=Q: X and Y taken together=Q:
R8 = -QCHoCCCnNRa iRZS; r2 1=H: R2 5 = 3-rphenvlethvnvnphenvl
The compound resulting from Example 100 is activated as in Example
30 101 and then treated with 3-phenylethynylaniline instead of N-benzyl-O-methyl-
hydroxylamineto give the title compound.
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Example 132
Formula VII: R JUCFh: R2=R2=f^%niil£ 4 ^I^ 5 Jzi^l together=Q:
and R 2 taken together=Q: X and Y taken together=Q:
R&= -OCH 2 CrO^NR24R2i : R ^CHoCEbCHoOH: R21= 4-fluoronhenvl
The compound resulting from Example 100 is activated as in Example
101 and then treated with (4-fluoroanilino)-l-propanol instead of N-benzyl-O-
methyl-hydroxylamineto give the title compound.
Example 133
Formula VII: R%CH 3 iR2=R%HlR3=OH; Rl and R5 . taken together=Q:
R6 and R l taken together=Q: X and Y taken together=Q:
R8= -O CHoCfO)NR2 4R25 ; R ^CHoCHoCHoOCOCHoCH oCOoH:
R25 = 4-fluorophenvl.
The compound resulting from Example 132 is treated with succinic
15 anhydride, by the procedure described in Tetrahedron Letters, 30: 5045-48
(1989), to give the title compound.
Example 134
Formula VII: R%CH 3 iR2=R%HiR^QH; Rl an d R l taken together=Q:
20 R£ and R l taken together=Q: X and Y taken together=Q:
Rg= -QCHoCrO)NR24R2i^R24 and R 2 j are taken together as the fo i 1owinp
diradical. -CHoCHoCfOr^CHoO^CHoCHo-
The compound resulting from Example 100 is activated as in Example
101 and then treated with l,4-dioxa-8-azaspiro[4.5]decane instead of N-benzyl-
25 O-methyl-hydroxylamineto give the title compound.
Example 135
Formula VTT: Ri=CT 3 l£%R%HlR%^H; R4 and R i taken together=Q-
R£ and R2 taken together=Q: X and Y taken together=Q-
30 RS = -OCH 2 C(0)NHNH-CO-<-4-nvridvn
The compound resulting from Example 100 is activated as in Example
101 and then treated with isonicotinic acid hydrazide instead of N-benzyl-O-
methyl-hydroxylamineto give the title compound.
-118-
Example 136
Formula VII: R l =CFh : R2=R 2=H: R2=0H: Rl and Rl taken together=Q:
R 6 and Rl taken together=Q: X and Y taken together=Q:
R S= -OCHoCfOINR^ RlS; R24 =H: R25=3-fruorophenvl
The compound resulting from Example 100 is activated as in Example
101 and then treated with /n-fluoroaniline instead of N-benzyl-O-methyl-
hydroxylamine to give the title compound.
Example 137
Formula VII: Rl=CH 2 : R2=R 2=H: R2=OH: R4 and R5 taken together=Q:
R £ and Rl taken together=Q: X and Y taken together=Q:
R £= -OCH 2 CrO)NR2 4R2i : r24 = H: R 2S= 3-hvdroxv-phenvl
The compound resulting from Example 100 is activated as in Example
101 and then treated with w-aminophenol instead of N-benzyl-O-methyl-
hydroxylamineto give the title compound.
Example 138
Formula VII: Rl=CFfr; R2=Rg=H: R2=0H: Rl and R5 taken together=Q:
R 6 and Rl taken together=Q: X and Y taken together=Q:
R8 = -OCHoCfO^NRM RZa. R24 and R 2j are taken together as the following
diradical: -CHoCFb-NrCFhVCHoCH o-.
The compound resulting from Example 100 is activated as in Example
101 and then treated with N-methylpiperazine instead of N-benzyl-O-methyl-
hydroxylaminet o give the title compound.
Example 139
Formula VII: R l =CFh : R2=R 2=H: R2=0H: R± and Ri taken together=Q:
R £ and Rl taken together=Q: X and Y taken together=Q:
R S= -OCH2C(0->NR2 4r2S : r ^H: r2 5 = 1.4-benzodioxan-6-vl
The compound resulting from Example 100 is activated as in Example
101 and then treated with l,4-benzodioxan-6-amine instead of N-benzyl-O-
methyl-hydroxylamine to give the title compound.
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Example 140
Formula VIT: R%CH 3 iR2 s R%H^r3 s QHiR4 and R s taken togethe r = 0:
_R£ and RZ taken together =Q: X and Y taken together=Q:
R£= -O^CfQNRMR^^H; R2 % l,3-benzodinxnl-<i-vl
5 The compound resulting from Example 100 is activated as in Example
101 and then treated with 3,4-(methylenedioxy)-aniline instead of N-benzyl-O-
methyl-hydroxylamine to give the title compound.
Example 141
10 Formula VTI: R%CH 3 ^R%E%HlE^QHiR4 and R 5 taken together^:
R6 and Rl taken together= Q: X and Y taken togethe.r=Q
&S= -OCH 7 C(Q)NR24r2S i r24^ h . r2 5= i-nanhthalenvl
The compound resulting from Example 100 is activated as in Example
101 and then treated with 1-naphthylamine instead of N-benzyl-O-methyl-
15 hydroxylamineto give the title compound.
Example 142
Formula VII: R%CT 3 lR2^%H L R3=OH L R4_a nd R i taken togethRr=0:
Rfi and Rl taken together=Q; X and Y taken together=Q:
20 R £= -OCHoaO)-a-nvrrnliHmvn
The compound resulting from Example 100 is activated as in Example
101 and then treated with pyrrolidine instead of N-benzyl-O-methyl-
hydroxylamine to provide the title compound.
25 Example 143
Formula VII: Rl^3lR%R%HLR%OHLR^_and R l taken together=Q:
R6 and Rl taken together=Q- X and Y taken togethe.r=Q;
R g= -QCHoCfOWl -p ippHHinyl)
The compound resulting from Example 100 is activated as in Example
30 101 and then treated with piperidine instead of N-benzyl-O-methyl-
hydroxylarnine to provide the title compound.
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Example 144
Formula VII: Rl=CH r. R2=R 2=H: R3=OH: Rl and R-S taken together=Q:
R6 and Rl taken together=Q: X and Y taken together=Q:
R &= -QCH 2 C(-Q')OCH2-f9-fluorenvn
5 Rapamycin (1 1.0 g, .012 mol) is dissolved in distilled CH 2 Cl2 (50 mL).
Rhodium (II) acetate dimer (100 mg) is added and the mixture cooled to 0 °C. 9-
Fluorenylmethyl diazoacetate (3.35 g, .012 mol) is dissolved in CH2CI2 (10 mL)
and the solution added to the reaction via syringe pump at a rate of
approximately 0.5 mL/hour. Addition is complete in approximately 24 hours.
10 The reaction is stirred at 0 °C for an additional 24 hours then loaded onto silica
(230-400 mesh, 400 g) and the solvent evaporated by airflow in the hood. The
adsorbed silica is layered over fresh silica (800 g) in a 1 L fritted glass funnel
and eluted with mixtures of CH2CI2 and CH3CN. Fractions containing product
are combined and concentrated to provide title compound.
15
Example 145
Alternate Preparation of
Formula VII: Rl^CH^ : R2=R g=H: R2=0H: Rl and RS taken together=Q:
R6 and R l taken together=Q: X and Y taken together=Q: R&= -OCPfrCfO'lOH
20 The resultant product of Example 144 is dissolved in CH2CI2, whereupon
piperidine is added. The solution is stirred at room temperature for 2 hours then
transferred to a separatory funnel, diluted with additional CH2CI2 (100 mL), then
washed with 1 N HC1 (2 x 100 mL) and brine (2 x 100 mL). The organic layer is
dried (Na2SC>4), filtered, and the solvent removed in vacuo to give crude title
25 compound with is purified by chromatography on silica gel.
Example 146
Formula VII: R l^CH?: R2=R9 =H: R2=QH: Ri and R 5 - taken together=Q:
R & and Rl taken together=Q: X and Y taken together=Q:
30 R £= -OCH9C(C0NR2 4r25 : r ^h- R 2 5 = -CH 2 CH 2 C f H 1
The compound resulting from Example 145 is dissolved in
dichloromethane and the solution cooled to 0 °C. HOBT - H2O is added followed
by EDAC then phenethylamine. The reaction is warmed to room temperature
and stirred overnight. Dichloromethane is added and the organic phase washed
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with 1 N HC1, saturated sodium bicarbonate solution, and then brine. The
organic layer is dried (Na2SC>4), filtered, and solvent removed in vacuo to give
crude product. This is purified by HPLC (20 x 300 mm silica column) eluting
with 3:1 hexane-acetone. Fractions containing product are combined and solvent
5 removed in vacuo to give the title compound.
Example 147
Formula VII: R%CH3iR2=R%HlR3=QH; Rl and R j taken t ogether=Q:
R£ and R l taken together=Q: X and Y taken together=Q-
10 R &= -OCH 2 CrO^NR2 4 R 2i : R24— qch,. r2 5 = -CH^ClhCxH * ~
The title compound is prepared using the procedures described in
Example 146 and substituting N,N-methyloxy, 2-phenylethyl amine for
2-phenylethylamine.
15 Example 148
Formula VII: Rl^CH^; r2=r2=H: R2=QH: Rl an H taken together=Q:
R£ and R 2 taken together=Q: X and Y taken together=Q:
R S= -QCHoCfOtNHfnWo^NH-dansvl
The title compound is prepared using the procedures described in
20 Example 146 and substituting dansyl cadaverine for 2-phenylethylamine.
Example 149
Formula VII: Rif^H3iR2^%H^=QH: r4 and R5 taken together=Q:
25 R£ and R l taken together=Q: X and Y taken together=Q:
R S= -OCH 2 CfO^NR2 4F!2S. R24=h-_r2%-£^
The title compound is prepared using the procedures described in
Example 146 and substituting aniline for 2-phenylethylamine.
30
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Example 150
Formula VII: Rl=CH 2 ; R2=R9 =H: R2=OH: Rl and R5 taken together=Q:
R £ and RX taken together=Q: X and Y taken together=Q;
R S= -OCH2CfO)NHfCH2^2NfCH2CH2^20
5 The title compound is synthesized in the manner described for Example
101 substituting 2-(4-morpholino)-ethylamine for N-benzyl-O-methyl-
hydroxylamine.
Example 151
10 Formula VII: R^CH r R2=R £=H: R2=QH: Rl and Ri taken together=Q:
R £ and Rl taken together=Q: X and Y taken together=Q:
R S= -OCH 2 Cf O^NHfCH2^N(CH2CH2V?Q
The title compound is prepared using the procedures described in
Example 146 and substituting 3-(4-morpholino)-propylamine for 2-
15 phenylethylamine.
Example 152
Formula VII: Rl=CKh: R2=R2=H: R2=0H: Rl an d R5 taken together=Q:
R 6 and Rl taken together=Q: X and Y taken together=Q:
20 R &= -OC^CfOlNHfCF^NfCFh V?
The title compound is synthesized in the manner described for Example
101 substituting 2-dimethylamino-ethylamine for N-benzyl-O-methyl-
hydroxylamine.
25
Example 153
Formula VII: R l =CFh : R2=r9 =H: Rl=OH: Rl and R5 taken together=Q:
30 R fi and Rl taken together-O: X and Y taken together=Q:
RS = -OCH 2 C('0')NR2 4r2^ : r24 =H : R^ -fCHotaNfCHafc
The title compound is prepared using the procedures described in
Example 146 and substituting 3-dimethylamino-propylamine for 2-
phenylethylamine.
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Example 154
Formula VII: Rl=CBh: R2=R2=H: R2=0H: R4 an d Rl taken together=Q:
R 6 and Rl taken together=Q; X and Y taken together=Q:
5 R ^-OCHoCfOVrfSVHNCHrCHoCfi H ^CO^CHoPh^-OMe^
The title compound is prepared using the procedures described in
Example 146 and substituting L-phenylalanine p-methoxybenzylester for 2-
phenylethylamine.
10 Example 155
Formula VII: Rl=CHh: R2 =R 2=H: R3=QH: R4 and R l taken together=Q:
R & and Rl taken together=Q: X and Y taken together=Q:
R ^ -OCHoaOVrfSVHNCHfCHoCg H OCCbHI
The title compound is synthesized in the manner described in Example
15 100 substituting the product from Example 154 for the product from Example
99.
Example 156
Formula VII: Rl =CHr. R 2=R2=H: r3=OH: Rl and R l taken together=Q:
20 R 6 and Rl taken together=Q: X and Y taken together=Q:
RS =-OCH2C(OVrCRVHNCHrCH2C^ H OC0 2 CH2Phf4-OMe^
The title compound is synthesized in the manner described for Example
146 substituting D-phenylalanine p-methoxybenzylester for 2-phenylethylamine.
25
Example 157
Formula VII: Rl=CH 2 : R2=R 2=H: R2=OH: Rl and R l taken together=Q:
30 R 6 and Rl taken together=Q; X and Y taken together=Q:
R &=-OCH2C(OVr(RVHNCH(CH2 C f H^m 2 Hl
The title compound is synthesized in the manner described in Example
100 substituting the product from Example 156 for the product from Example
99.
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Example 158
Formula VII: Rl=CHr . R 2=R2=H: R2=0H: R4 and R 5 - taken together=Q:
R 6 and Rl taken together=Q: X and Y taken together=Q:
5 R &= -OCH 2 C(-O^NR2 4r2S : r ^H: rZ^cHoVtSH
The product of Example 100 (1.4 g, 1.4 mmol) is dissolved in THF (4.5
mL) and the solution cooled to 0 °C before adding N-methylmorpholine (155.1
|iL, 1.4 mmol) followed by isobutyl chloroformate (122.2 pL, 1.4 rnmol). The
resulting suspension is stirred for 20 minutes at 0 °C then 2-aminoethanethiol
10 hydrochloride (320.8 mg, 2.8 mmol) is added. The mixture is stirred for 3 hours
at room temperature before addition of more N-methylmorpholine (387.8 |iL, 3.5
mmol). The reaction is stirred overnight, loaded onto silica (40 mL) in a fritted
funnel, then eluted with dichloromethane (100 mL), 1:1 hexane/acetone (200
mL), followed by acetone (100 mL). Fractions containing product are combined
15 and solvent removed in vacuo to give crude product This material is further
purified by HPLC (30 x 300 mm silica column) eluting with 2:1 hexane/acetone
to provide the title compound.
Example 159
20 Formula VII: Rl^CH^ : R 2=R9=H: R2=OH: R± and Ri taken together=Q:
Rfi and Rl taken together=Q: X and Y taken together=Q:
R &= -OCH2C(Q)NR2 4R2j : r24 = H: rZ^ch^ sh
The tide compound is synthesized in the manner described for Example
158 substituting 3-amino-propanethiol for 2-aminoethanethiol.
25
Example 160
Formula VII: R l =CFh: R2=RS=H: Rl=OH: R4 and R5 taken together=Q:
30 R 6 and R2 taken together=Q: X and Y taken together=Q:
r £= -ocH^c^O'tort-butvn
Silver (I) oxide (926 mg, 4.0 mmol) is added to rapamycin (791 mg, 1.0
mmol) dissolved in acetonitrile (0.8 mL) and t-butyl iodoacetate (828 (iL, 7.0
mmol). The mixture is stirred at room temperature for 5 days, volatiles are
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removed in vacuo. The product is isolated by chromatography on silica gel as
described in Example 98.
Example 161
5 Formula VTT: Ri=CFh; r2=r2= H : R2=0H: R4 an H R l taken together=Q:
R^ and R l taken together=Q: X and Y taken together=Q:
R 3= -OCH 2 Cf(r)NR2 4R2S : R^H: R2 S= 2-naohthvl
The compound resulting from Example 100 is activated by the procedure
described in Example 101 and then treated with 2-naphthylamine instead of N-
10 benzyl-O-methyl-hydroxylamine to give the tide compound.
Example 162
Formula VII: R%CH3iR2=R%HlR3=QH; Ri and R 5 taken together=Q:
R6 and R l taken together=Q: X and Y taken together=Q:
15 RS= -OCH 2 CfO\NR24R25 : R^h- R ^.fHoNSO^phenvl
The compound resulting from Example 100 is activated by the procedure
described in Example 101 and then treated with sulfanilamide instead of N-
benzyl-O-methyl-hydroxylamineto give the tide compound.
20 Example 163
Formula VII: Rl5^1lR%£S=HlR2=OH; R4 and R l taken toge-,the.r=Q-
R6 and R l taken together=Q: X and Y taken topether=Q:
Rg=-OCHoCrO )-('4-<'2-hvdroxvethvnninRrzin-l-vl')
The compound resulting from Example 100 is activated by the procedure
25 described in Example 101 and then treated with N-(2-hydroxyethyl)-piperazine
instead of N-benzyl-O-methyl-hydroxylamine to give the title compound.
Example 164
Formula VII: R l=CH ? : R^Rg^^j^nR^^^^St^^
together=Q:
R£ and R l taken together=Q: X and Y taken toeether=Q:
R S= -OCH 2 Cr(T)NR2 4R25 r RT^r^^ZS^^^
The compound resulting from Example 100 is activated by the procedure
described in Example 101 and then treated with N-methylaniline instead of N-
benzyl-O-methyl-hydroxylamine to give the title compound.
30
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Example 165
Formula VTT: Rl =CH 2 ; K2^%H^3=nHjP4«^5_gi^
together=Q:
R6 and R l taken together=Q: X and Y taken together=Q:
5 R&= -OCH 2 CfO>NR2 4 R 2a : r24^ R 2 W CHzCH2 q H
The compound resulting from Example 100 is activated by the procedure
described in Example 101 and then treated with N,N-bis-(2-hydroxyethyl)-amine
instead of N-benzyl-O-methyl-hydroxylamineto give the title compound.
10 Example 166
Formula VII: Ri=CH 3 iR2=R2=HLR^OH; R± and R i taken together=Q
R6 and R2 taken togerher=Q; X and Y taken together=Q:
R3= -OCH 2 CrO^NR24 R 2i : r^ch, r2 ^ -CHoCFhCHoNf fH ^Vi
The compound resulting from Example 100 is activated by the procedure
15 described in Example 101 and then treated with N,N'-methyl-
(3-dimethylaminopropyl)-amine instead of N-benzyl-O-methyl-hydroxylamineto
give the title compound.
Example 167
20 Formula VII: R%CH^2=R%HlR2=QHi Rl and R 5 taken together^O-
R£ and R l taken together=Q: X and Y taken together=Q
RS= -OCH 2 CrO^NRM R 2^^24^ D he nyL R2 S = -CH z CH z CH oOH
The compound resulting from Example 100 is activated by the procedure
described in Example 101 and then treated with N,N-phenyl-(3-hydroxypropyl)-
25 amine instead of N-benzyl-O-methyl-hydroxylamineto give the title compound.
Example 168
Formula VII: R^CHsi^^^H^^QH^i^pd R 5 taken t0g ether=O:
30 R6 and Rl taken togerhe r=Q; X and Y taken together^
R&= -OCH 2 CrQ^NR24 R 2S. R 24 =H: rI ^.ch^^ qh^
The compound resulting from Example 100 is activated by the procedure
described in Example 101 and then treated with serinol instead of N-benzyl-O-
methyl-hydroxylamine to give the title compound.
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Example 169
Formula VII: R%CH 3 iR2=R%H l R^QHi_R1 and R etaken together=Q:
BAand R 2 taken together=Q: X and Y taken topether=Q:
5 R 3= -OCH 2 CfQ^NR2 4R2S r R2%^25^££Zlljltel
The compound resulting from Example 100 is activated by the procedure
described in Example 101 and then treated with 3-trifluoromethylaniline instead
of N-benzyl-O-methyl-hydroxylamine to give the title compound.
10 Example 170
Formula VIT: RJ^CHsiR^S^R^CTjLR^nd R 5 taken together=0:
_Rfi and Rl taken together=Q: X and Y taken toge.ther=Q-
R £= -OCH 2 CrO)NR2 4R25. : r^rI ^ -CH 2 CN
The compound resulting from Example 100 is activated by the procedure
15 described in Example 101 and then treated with iminodiacetonitrile instead of N-
benzyl-O-methyl-hydroxylamineto give the title compound.
Example 171
Formula VII: R%CH 31 R2^%H l r2=QH l r4 _ and R 5 taken togt . t hrr=n-
20 R^_and R 2 taken together=Q: X and Y taken toPethex=r>
R &= -OCHoCrOVn- a7 iriHinyn
The compound resulting from Example 100 is activated by the procedure
described in Example 101 and then treated with aziridine instead of N-benzyl-O-
methyl-hydroxylamine to give the title compound.
Example 172
Formula VII: R i^CHBjRZ^HLRa^OHLR^and R i taken together=Q-
R6 and R l taken together=Q: X and Y taken tngether=Q:
R £= -OCH z NHrrOVr4-momho1invn
The compound resulting from Example 100 (564 mg, 0.58 mmol) in THF
(6 mL) is stirred together with N-methylpiperidine (73 ]iL, 0.58 mmol) and
diphenylphosphorylazide (73 (iL, 0.58 mmol) at ambient temperature for 5
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minutes, then at reflux for 3 hours. The stirring solution is cooled to ambient
temperature and treated with morpholine (157 (J.L, 1.8 mmol). The mixture is
purified by HPLC on a column 20 x 300 mm (YMC 15u, 60 A spherical Si0 2 )
eluting with a step gradient of hexaneracetone (1:1) then hexane:acetone (2:3), to
5 provide title compound.
Example 173
Formula VII: R l=CH 2 : R2=R g=H: R2=OH: Rl and R 5 taken together=Q:
R 6 and RZ taken together=Q: X and Y taken together=Q:
10 R &= -OCH2NHCfO)NR2 4R25. : r ^h- R^phenyi
The compound resulting from Example 100 is activated as in Example
172 and then treated with aniline instead of morpholine to give the title
compound.
15 Example 174
Formula VII: R l=CH^: R2=R2=H: R2=0H: Rl anc \ R j taken together=Q:
R 6 and Rl taken together=Q: X and Y taken together=Q:
R& = -OCHoNHCrOVphenvI
The compound resulting from Example 100 is activated as in Example
20 172 and then treated with benzoic acid instead of morpholine, whereupon the
mixture is heated. Purification by chromatography on silica gel provides the title
compound.
Example 175
25 Formula VII: Rl=CH 2 : R2=r 2=H: R2 =0H: Rl an d R i taken together=Q:
R £ and Rl taken together=Q: X and Y taken together=Q:
R &= -OCH 2 NHCfCnNR2 4R2S : R2 4= H: R^-CIfrCHoCHoOH
The compound resulting from Example 100 is activated as in Example
172 and then treated with 3-aminopropanol instead of morpholine to give the title
30 compound.
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Example 1 76
Formula VII: R^CH^a^Rg^R^QH^Rl and R $ taken togethRr=0;
R^and RZ taken togethp.r= Q: X and Y taken together):
R%^QCH 2 C£0)NK 2 ^R^iR2%Hi
5 R2£= 6-carbornethnx vmethvlrnercaptopurine hvdrazid-vl
The compound resulting from Example 100 is activated as in Example
101 and then treated with 6-carbomethoxymethylmercaptopurine hydrazide
instead of N-benzyl-O-methyl-hydroxylamineto give the title compound.
10 Example 177
Formula VIT: K l=££^2 E g2=£^2^Q H ^ Jsnd R l taken togetnRr=n .
R£ and Rl taken together^ X and Y taken t 0g ether=:O:
Rg= -OCH,C(Q)NR24R2S^R24_and R21 are taken tether as the fmi^ w „
diradical: -CHoPHoSr ^CHoCH o-
15 The compound resulting from Example 100 is activated as in Example
101 and then treated with thiomorpholine sulfone instead of N-benzyl-O-methyl-
hydroxylamineto give the title compound.
Example 17R
20 Formula VIT: R %£H3lR%E%H 1 R3=QH L _R^ and R S taken tnpe.th^o-
Rfi_and Rl taken together^O] X and Y taken together=Q:
R&= -OCH 2 C(0)NR24R2S L R24^ H . R ^CH.CHo-^-F-p h.nyn
The compound resulting from Example 100 is activated as in Example
101 and then treated with 4-fluorophenethylarnine instead of N-benzyl-O-
25 methyl-hydroxylamine to give the title compound.
Example 1 79
Formula VTT: R i=CT3lR%R%HLE%QHLRl and R i taken together^-
B& and Rl taken together^ Q: X and Y taken togethe.r=(>
RS= -OCH 2 C(0)NR24r2S 1 r24=h. R 2 5 =4 . cl _ Dhenv1
The compound resulting from Example 100 is activated as in Example
10 1 and then treated with 4-chloro aniline instead of N-benzyl-O-methyl-
hydroxylamineto give the title compound.
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Example 180
Formula VII: R%CH3lR2=R%HiR3=QH; R4 and taken together=Q:
R6 and R Z taken together=Q: X and Y taken together=Q:
R Z= -QCH 2 CfQ-)NR2 4R25 ; Ra^H^l^d^nQ^^^j^h^
5 The compound resulting from Example 100 is activated as in Example
101 and then treated with 4-methoxyaniline instead of N-benzyl-O-methyl-
hydroxylamine to give the title compound.
Example 181
10 Formula VII: R%CH 3 iR2=r2=H l r3^QHiR4 and r5 _ ta ken together=Q:
R_£ and R l taken together=Q: X and Y taken together=Q-
R £= -OCH 2 CrO->NR2 4 R 2i. r^H: R2 S =3 . I . phenv1
The compound resulting from Example 100 is activated as in Example
101 and then treated with 3-iodoaniline instead of N-benzyl-O-methyl-
15 hydroxylamineto give the title compound.
Example 182
Formula VII: R%CH 3 'iR2=R%HlR3^0HiR4 and R 5 taken togethe,r=Q-
Rfi and Rl taken together= Q: X and Y taken togethe.r=Q;
20 R ^-OCHoCfO^O-CHo-rnRVf+Valnha-pinen-IO-vm
(a) A three-neck 2 L roundbottom flask equipped with an overhead stirrer
was charged with diethylether (800 mL), chloroacetyl chloride (40 mL, 0.5 mol)
and (lR)-(-)-nopol (85.3 mL, 0.5 mol). At 0 °C, triethylamine (69.5 mL, 0.5
mol) was added dropwise over 15 minutes. After stirring at 0 °C for 1 hour, the
25 mixture was warmed to ambient temperature and stirred for 18 hours. The
mixture was vacuum filtered through a Buchner funnel and the white cake was
extracted with ether (2 x 200 mL). The filtrates were then washed sequentially
with 0.5 N HC1 (500 mL), water (500 mL) and brine (500 mL). After drying the
organics (Na2SC>4), the mixture was filtered and concentrated to a pale tan oil
30 (104 g). The resultant nopol chloroacetate was sufficiently pure to carry forward
in the next step.
(b) Sodium Iodide (20.1 g, 134 mmol) was refluxed in acetone (55 mL)
for 5 minutes and cooled to room temperature. Nopol chloroacetate from step (a)
(5.85 g, 24.17 mmol) was added, and the reaction was stirred for 30 minutes.
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The solvent was removed in vacuo, and the resulting slurry was partitioned
between water (30 mL) and ethyl acetate (20 mL). The aqueous portion was
extracted with additional ethyl acetate (20 mL). The combined organics were
washed sequentially with saturated sodium bicarbonate (30 mL) and 10% sodium
5 bisulfite (30 mL), dried (sodium sulfate) and concentrated in vacuo to an amber
oil (7 g). The resulting nopol iodoacetate was sufficiently pure to use in the next
step.
(c) Rapamycin (2.9 g, 3.16 mmol) and nopol iodoacetate from step (b)
(5.70 g, 17.1 mmol, 5.4 eq) are dissolved in acetonitrile (1.5 mL). After a
10 homogeneous solution is obtained, it is cooled to 0 °C and silver(I) oxide (3. 13 g,
13.4 mmol) is added portion wise (15 minutes). The solution is brought to room
temperature by gradual melting of the ice and is stirred for 5 days. The reaction
is diluted in diethyl ether and poured onto silica gel (70-230 mesh, 20 mL) and
allowed to air dry. The adsorbed silica is layered on fresh silica (70-230 mesh,
15 100 mL) and eluted with methylene chloride (150 mL); methylene
chlorideracetonitrile (9:1, 450 mL); (3:1, 300 mL); (1:1, 200 mL); acetone (200
mL). 50 mL fractions are collected. Fractions containing product are pooled,
concentrated, further purification by HPLC on silica eluting with 3:1
hexane:acetone provides pure title compound.
20
Example 183
Formula VII: RI^CHsiR^R^HlR^OH; Ri and R l taken together=Q:
R£ and Rl taken together=Q: X and Y taken together=Q:
R g= -OCHoCrO^O-CHo-^-nitrophenvll
25 (a) A three-neck 2 L roundbottom flask equipped with an overhead stirrer
was charged with diethylether (800 mL), chloroacetyl chloride (40 mL, 0.5 mol)
and 4-nitrobenzylalcohol (76.5 g, 0.5 mol) and cooled to 0 °C. Triethylamine
(69.5 mL, 0.5 mol) was added dropwise over 15 minutes. After stirring at 0 °C
for 1 hour, the mixture was warmed to ambient temperature and stirred for 18
30 hours. The mixture was vacuum filtered through a Buchner funnel and the white
cake was extracted with ether (2 x 200 mL). The filtrates were then washed
sequentially with 0.5 N HC1 (500 mL), water (500 mL) and brine (500 mL).
After drying the organics (Na 2 S0 4 ), the mixture was filtered and concentrated to
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a pale tan solid (74.8 g). The crude product was recrystallized from diethylether.
m.p. 71-72 °C.
(b) Sodium Iodide (39.5 g, 260 mmol) was refluxed in acetone (104 mL)
for 3 minutes and cooled to room temperature. 4-Nitrobenzyl chloroacetate
5 from step (a) (10.7 g, 47 mmol) was added, and the reaction was stirred for 30
minutes. The solvent was removed in vacuo, and the resulting slurry was
partitioned between water (50 mL) and ethyl acetate (50 mL). The aqueous
phase was extracted with additional ethyl acetate (50 mL), and the combined
organics were washed sequentially with saturated sodium bisulfite (2 x 50 mL)
10 and brine (50 mL). The organics were dried (sodium sulfate) and concentrated in
vacuo to pure product (15.6 g).
(c) Rapamycin (5.8 g, 6.3 mmol) and 4-nitrobenzyl iodoacetate from step
(b) (15.6 g, 48.6 mmol, 7.7 eq) are dissolved in acetonitrile (2.5 mL). After a
homogeneous solution is obtained, it is cooled to 0 °C and silver(I) oxide (5.9 g,
15 25.6 mmol) is added portionwise (15 minutes). The solution is brought to room
temperature by gradual melting of the ice and is stirred for 5 days. The reaction
is diluted in diethyl ether (25 mL), poured onto silica gel (70-230 mesh, 40 mL)
and allowed to air dry. The adsorbed silica is layered on fresh silica (70-230
mesh, 200 mL) and eluted with methylene chloride (500 mL); methylene
20 chlorideracetonitrile (9:1, 400 mL); (6:1, 300 mL); (3:1, 1000 mL); (1:1, 500
mL); (1:2, 300 mL). 100 mL fractions are collected. Fractions containing
desired product (CH 2 C1 2 :CH 3 CN 3:1) are pooled and concentrated in vacuo to
provide the title compound.
25 Example 184
Formula VTT: R%CH 3 iR2=r2=H 1 r3=QHlR4 and R S taken together=Q:
R6 and Rl taken togethfir= Q; X and Y taken together=0-
R&= -OCH^C(0)NK24R2£ ; R24 = . (CH2 > lNfCH: , rH2 ^ 0 . R ^-CHoCFbOH
The tide compound is synthesized by the procedures described in
30 Example 101 substituting N,N-[2-hydroxyethyl][2-(4-morpholino)-ethyl]amine
for N-benzyl-O-methyl-hydroxylamine.
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20
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Example 185
Formula VTT: R%CH3iR2^R%HlR^OH^R4 and R 5 taken together=Q:
RAand RZ taken togethe r^Oj X and Y taken together=Q:
2.3.4.6- tetra-O-acetvl-beta-D-glucopvranosvloxv
Alpha-D-glucopyranosyl bromide tetraacetate (2.46 g, 6 mmol) and
rapamycin (913 mg, 1.0 mmol) in acetonitrile (1 raL) at 0 °C is treated with
Ag 2 0 (928 mg, 4 mmol). The mixture is warmed to ambient temperature and
stirred for 5 days. Purification of the mixture by chromatography on silica gel
provides the title product.
Example 186
Formula VTT: Fi -^CHgLR^^HLR^OH; Ri and R i taken togeth^O-
RSand RZ taken together=Q; X and Y taken together=Q-
R&= 2,3,4,6-tetra-O-a cetvl-heta-D-glucopvranosvloxv
15 Alpha-D-glucopyranosyl bromide tetraacetate (1.23 g, 3 mmol),
rapamycin (913 mg, 1.0 mmol) and crushed 4A molecular sieves (2 g) in
anhydrous methylene chloride (150 mL) at -78 °C is treated with AgC0 3 (1.7 g,
10 mmol) followed by Ag(OS0 2 CF 3 ) (257 mg, 1.0 mmol). The mixture is
warmed to ambient temperature over 8 hours and is stirred for an additional 5
hours. Purification of the mixture by chromatography on silica gel provides title
product.
Example 187
25 Formula VTT: R %CH3iR2^%H l r3^qh l r4 _ and R 5 taken tog ether=Q
RA and RZ taken together=Q- X and Y taken together=Q:
r S= -ocHofYrnorHorr-K
The title compound is prepared using the procedures described in
Example 183 substituting 2,2,2-trichloroethanol for p-nitrobenzylalcohol.
30
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Example 188
In vitro Assay of Biological Activity
The immunosuppressant activity of the compounds of the present
invention was determined using the human mixed lymphocyte reaction (MLR)
5 assay described by Kino, T. et al. in Transplantation Proceedings, XIX(5):36-
39, Suppl. 6 (1987). The in vitro immunosuppressant activity of the compounds
of the present invention was determined in a one way allogeneic mixed leukocyte
response (MLR) assay using rat lymph node and spleen cells, conducted as
follows: Responder cells were obtained from the lymph nodes of Brown Norway
10 rats (Harlan Sprague Dawley, Inc., Indianapolis, IN) and the stimulator cells
were isolated from the spleens of Lewis rats (Harlan Sprague Dawley, Inc.,
Indianapolis, IN). 200-250 gram rats were sacrificed by asphyxiation with CO2
and the popliteal and mesenteric lymph nodes or spleen were removed by sterile
dissection. The tissue was placed in RPMI 1640 supplemented with 10%
15 heat-inactivated fetal bovine serum, 2 mM L-glutamine, 50 (J.M
2-mercaptoethanol, 50 units/mL penicillin G, and 50 ng/mL streptomycin
(complete RPMI medium). After mechanically disrupting the tissue and
allowing debris to settle at 1 x g, the suspended cells were aspirated. The cell
suspensions were centrifuged 10 min at 400 x g and the responder cells
20 resuspended in complete RPMI medium at 2 x 10 6 cells/mL. To remove red
cells, the spleen cells were suspended in 0.14 M NH4CI/O.OI7 M Tris-HCl lysing
buffer, pH 7.4, for 2 minutes, mixed with RPMI 1640, and centrifuged as before.
The spleen cells were subsequently washed three times by centrifugation in
RPMI 1640. To inhibit their abilty to proliferate, spleen cells were suspended at
25 1 x 10 7 cells/mL in complete RPMI medium and incubated in the presence of 25
|J.g/mL of mitomycin C for 30 minutes at 37 °C. The mitomycin C-treated spleen
cells were washed three times by centrifugation in RPMI 1640 before being
suspended in complete RPMI medium at 4 x 10 6 cells/mL.
For the MLR, 1 x 10 5 lymph node cells were mixed with 5 x 10 5
30 mitomycin C-treated spleen cells in 0.2 raL of complete RPMI 1640 and cultured
in 95% air / 5% CO2 atmosphere for 120 hours at 37 °C. Test compounds were
dissolved at 10 mM in dimethylsulfoxide, diluted in complete RPMI medium,
and 25 u\L of the test compound was added to the lymph node cells before
addition of the spleen cells. During the final 6 hours, the cells were labeled with
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0.5 flCi per well of tritiated thymidine ( 3 H-TdR; DuPont NEN Research
Products, Boston, MA). The cells were harvested by vacuum filtration onto
glass fiber filters and the filter radioactivity measured with a MATRIX 9600
direct beta counter (Packard Instrument Company, Meriden, CT). To calculate
the compound concentration which caused 50% inhibition (IC 50 ) in an assay, the
inhibition data was fit to a log-logistic linear function.
The results of the assay, shown below in Table 1, demonstrate that the
compounds tested are effective immunomodulators at nanomolar concentrations.
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Table 1
Mixed Leukocyte Response (MLR)
Example Rat MLR IC sn fnM)
>
3
0.13
10
0.03
17
0.15
38
0.03
50
0.96
39
0.14
71
0.12
72
0.99
74
1.81
5 The compounds of the invention, including but not limited to those
specified in the examples, possess immunomodulatory activity in mammals
(especially humans). As immunosuppressants, the compounds of the present
invention axe useful for the treatment and prevention of immune-mediated
diseases such as the resistance by transplantation of organs or tissue such as
10 heart, kidney, liver, medulla ossium, skin, cornea, lung, pancreas, intestinum
tenue, limb, muscle, nervus, duodenum, small-bowel, pancreatic-islet-cell, etc.;
graft-versus-host diseases brought about by medulla ossium transplantation;
autoimmune diseases such as rheumatoid arthritis, systemic lupus erythematosus,
Hashimoto's thyroiditis, multiple sclerosis, myasthenia gravis, type I diabetes
15 uveitis, allergic encephalomyelitis, glomerulonephritis, and the like; and further
infectious diseases caused by pathogenic microorganisms, such as HIV. In the
particular cases of HIV- 1, HIV-2 and related retroviral strains, inhibition of T-
cell proliferation will suppress the replication of the virus, since the virus relies
upon the T-cell's proliferative functions to replicate. Further uses include the
20 treatment and prophylaxis of inflammatory and hyperproliferative skin diseases
and cutaneous manifestations of immunologically-mediated illnesses, such as
psoriasis, atopical dermatitis, contact dermatitis and further eczematous
dermatitises, seborrhoeis dermatitis, Lichen planus, Pemphigus, bullous
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pemphigoid, Epidermolysis bullosa, urticaria, angioedemas, vasculitides,
erythemas, cutaneous eosinophilias, Lupus erythematosus, acne and Alopecia
areata; various eye diseases (autoimmune and otherwise) such as
keratoconjunctivitis, vernal conjunctivitis, uveitis associated with Behcet's
5 disease, keratitis, herpetic keratitis, conical cornea, dystrophia epithelialis
corneae, corneal leukoma, ocular pemphigus, Mooren's ulcer, Scleritis, Graves'
opthalmopathy, Vogt-Koyanagi-Harada syndrome, sarcoidosis, etc.; reversible
obstructive airway disease, which includes conditions such as asthma (for
example, bronchial asthma, allergic asthma, intrinsic asthma, extrinsic asthma
10 and dust asthma), particularly chronic or inveterate asthma (for example, late
asthma and airway hyper-responsiveness), bronchitis and the like; inflammation
of mucosa and blood vessels such as gastric ulcers, vascular damage caused by
ischemic diseases and thrombosis. Moreover, hyperproliferative vascular
diseases such as intimal smooth muscle cell hyperplasia, restenosis and vascular
15 occlusion, particularly following biologically or mechanically mediated vascular
injury could be treated or prevented by the compounds of the invention. Other
treatable conditions include but are not limited to ischemic bowel diseases,
inflammatory bowel diseases, necrotizing enterocolitis, intestinal lesions
associated with thermal burns and leukotriene B4-mediated diseases; intestinal
20 inflammations/allergies such as Coeliac diseases, proctitis, eosinophilic
gastroenteritis, mastocytosis, Crohn's disease and ulcerative colitis; food-related
allergic diseases which have symptomatic manifestation remote from the gastro-
intestinal tract (e.g. migraine, rhinitis and eczema); renal diseases such as
interstitial nephritis, Goodpasture's syndrome, hemolytic-uremic syndrome and
25 diabetic nephropathy; nervous diseases such as multiple myositis, Guillain-Barre
syndrome, Meniere's disease, polyneuritis, multiple neuritis, mononeuritis and
radiculopathy; endocrine diseases such as hyperthyroidism and Basedow's
disease; hematic diseases such as pure red cell aplasia, aplastic anemia,
hypoplastic anemia, idiopathic thrombocytopenic purpura, autoimmune
30 hemolytic anemia, agranulocytosis, pernicious anemia, megaloblastic anemia and
anerythroplasia; bone diseases such as osteoporosis; respiratory diseases such as
sarcoidosis, fibroid lung and idiopathic interstitial pneumonia; skin disease such
as dermatomyositis, leukoderma vulgaris, ichthyosis vulgaris, photoallergic
sensitivity and cutaneous T cell lymphoma; circulatory diseases such as
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arteriosclerosis, atherosclerosis, aortitis syndrome, polyarteritis nodosa and
myocardosis; collagen diseases such as scleroderma, Wegener's granuloma and
Sjogren's syndrome; adiposis; eosinophilic fasciitis; periodontal disease such as
lesions of gingiva, periodontium, alveolar bone and substantia ossea dentis;
5 nephrotic syndrome such as glomerulonephritis; male pattern aleopecia or
alopecia senilis by preventing epilation or providing hair germination and/or
promoting hair generation and hair growth; muscular dystrophy; Pyoderma and
Sezary's syndrome; Addison's disease; active oxygen-mediated diseases, as for
example organ injury such as ischemia-reperfusion injury of organs (such as
10 heart, liver, kidney and digestive tract) which occurs upon preservation,
transplantation or ischemic disease (for example, thrombosis and cardiac
infraction): intestinal diseases such as endotoxin-shock, pseudomembranous
colitis and colitis caused by drug or radiation; renal diseases such as ischemic
acute renal insufficiency and chronic renal insufficiency; pulmonary diseases
15 such as toxinosis caused by lung-oxygen or drug (for example, paracort and
bleomycins), lung cancer and pulmonary emphysema; ocular diseases such as
cataracta, siderosis, retinitis, pigmentosa, senile macular degeneration, vitreal
scarring and corneal alkali burn; dermatitis such as erythema multiforme, linear
IgA ballous dermatitis and cement dermatitis; and others such as gingivitis,
20 periodontitis, sepsis, pancreatitis, diseases caused by environmental pollution
(for example, air pollution), aging, carcinogenis, metastasis of carcinoma and
hypobaropathy; diseases caused by histamine or leukotriene-C4 release; Behcet's
disease such as intestinal-, vasculo- or neuro-Behcet's disease, and also Behcet's
which affects the oral cavity, skin, eye, vulva, articulation, epididymis, lung,
25 kidney and so on. Furthermore, the compounds of the invention are useful for
the treatment and prevention of hepatic disease such as immunogenic diseases
(for example, chronic autoimmune liver diseases such as autoimmune hepatitis,
primary biliary cirrhosis and sclerosing cholangitis), partial liver resection, acute
liver necrosis (e.g. necrosis caused by toxin, viral hepatitis, shock or anoxia), B-
30 virus hepatitis, non-A/non-B hepatitis, cirrhosis (such as alcoholic cirrhosis) and
hepatic failure such as fulminant hepatic failure, late-onset hepatic failure and
"acute-on-chronic" liver failure (acute liver failure on chronic liver diseases), and
moreover are useful for various diseases because of their useful activity such as
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augmention of chemotherapeutic effect, cytomegalovirus infection, particularly
HCMV infection, anti-inflammatory activity, and so on.
Additionally, compounds of the invention possess FK-506 antagonistic
properties. The compounds of the present invention may thus be used in the
5 treatment of immunodepression or a disorder involving immunodepression.
Examples of disorders involving immunodepression include AIDS, cancer, senile
dementia, trauma (including wound healing, surgery and shock) chronic bacterial
infection, and certain central nervous system disorders. The immunodepression *
to be treated may be caused by an overdose of an immunosuppressive
10 macrocyclic compound, for example derivatives of 12-(2-cyclohexyl-l-
methylvinyl)-13, 19,21,27 -tetramethyl- 1 l,28-dioxa-4-azatricyclo[22.3.1.0 4 <9]
octacos-18-ene such as FK-506, or rapamycin. Overdosing of such medicants by
patients is quite common upon their realizing that they have forgotten to take
their medication at the prescribed time and can lead to serious side effects.
15 The ability of the compounds of the invention to treat proliferative
diseases can be demonstrated according to the methods described in Bunchman
ET and CA Brookshire, Transplantation Proceed. 23 967-968 (1991); Yamagishi,
et al., Biochem. Biophys. Res. Comm. 191 840-846 (1993); and Shichiri, et al., J.
Clin. Invest. 87 1867-1871 (1991). Proliferative diseases include smooth muscle
20 proliferation, systemic sclerosis, cirrhosis of the liver, adult respiratory distress
syndrome, idiopathic cardiomyopathy, lupus erythematosus, diabetic retinopathy
or other retinopathies, psoriasis, scleroderma, prostatic hyperplasia, cardiac
hyperplasia, restenosis following arterial injury or other pathologic stenosis of
blood vessels.
25 Aqueous liquid compositions of the present invention are particularly
useful for the treatment and prevention of various diseases of the eye such as
autoimmune diseases (including, for example, conical cornea, keratitis, dysophia
epithelialis comeae, leukoma, Mooren's ulcer, sclevitis and Graves'
ophthalmopathy) and rejection of corneal transplantation.
30
When used in the above or other treatments, a therapeutically effective
amount of one of the compounds of the present invention may be employed in
pure form or, where such forms exist, in pharmaceutically acceptable salt, ester
or prodrug form. Alternatively, the compound may be administered as a
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pharmaceutical composition containing the compound of interest in combination
with one or more pharmaceutically acceptable excipients. The phrase
"therapeutically effective amount" of the compound of the invention means a
sufficient amount of the compound to treat disorders, at a reasonable benefit/risk
5 ratio applicable to any medical treatment. It will be understood, however, that
the total daily usage of the compounds and compositions of the present invention
will be decided by the attending physician within the scope of sound medical
judgement. The specific therapeutically effective dose level for any particular
patient will depend upon a variety of factors including the disorder being treated
10 and the severity of the disorder; activity of the specific compound employed; the
specific composition employed; the age, body weight, general health, sex and
diet of the patient; the time of administration, route of administration, and rate of
excretion of the specific compound employed; the duration of the treatment;
drugs used in combination or coincidental with the specific compound employed;
15 and like factors well known in the medical arts. For example, it is well within
the skill of the art to start doses of the compound at levels lower than required to
achieve the desired therapeutic effect and to gradually increase the dosage until
the desired effect is achieved.
The total daily dose of the compounds of this invention administered to a
20 human or lower animal may range from about 0.001 to about 3 mg/kg/day. For
purposes of oral administration, more preferable doses may be in the range of
from about 0.005 to about 1.5 mg/kg/day. If desired, the effective daily dose
may be divided into multiple doses for purposes of administration; consequently,
single dose compositions may contain such amounts or submultiples thereof to
25 make up the daily dose.
The pharmaceutical compositions of the present invention comprise a
compound of the invention and a pharmaceutically acceptable carrier or
excipient, which may be administered orally, rectally, parenterally,
intracisternally, intravaginally, intraperitoneally, topically (as by powders,
30 ointments, drops or transdermal patch), bucally, or as an oral or nasal spray.
The phrase "pharmaceutically acceptable carrier" means a non-toxic solid, semi-
solid or liquid filler, diluent, encapsulating material or formulation auxiliary of
any type. The term "parenteral" as used herein refers to modes of administration
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which include intravenous, intramuscular, intraperitoneal, intrasternal,
subcutaneous and intraarticular injection and infusion.
Pharmaceutical compositions of this invention for parenteral injection
comprise pharmaceutically acceptable sterile aqueous or nonaqueous solutions,
5 dispersions, suspensions or emulsions as well as sterile powders for
reconstitution into sterile injectable solutions or dispersions just prior to use.
Examples of suitable aqueous and nonaqueous carriers, diluents, solvents or
vehicles include water, ethanol, polyols (such as glycerol, propylene glycol,
polyethylene glycol, and the like), carboxymethylcellulose and suitable mixtures
10 thereof, vegetable oils (such as olive oil), and injectable organic esters such as
ethyl oleate. Proper fluidity can be maintained, for example, by the use of
coating materials such as lecithin, by the maintenance of the required particle
size in the case of dispersions, and by the use of surfactants.
These compositions may also contain adjuvants such as preservatives,
15 wetting agents, emulsifying agents, and dispersing agents. Prevention of the
action of microorganisms may be ensured by the inclusion of various
antibacterial and antifungal agents, for example, paraben, chlorobutanol, phenol
sorbic acid, and the like. It may also be desirable to include isotonic agents such
as sugars, sodium chloride, and the like, Prolonged absorption of the injectable
20 pharmaceutical form may be brought about by the inclusion of agents which
delay absorption such as aluminum monostearate and gelatin.
In some cases, in order to prolong the effect of the drug, it is desirable to
slow the absorption of the drug from subcutaneous or intramuscular injection.
This may be accomplished by the use of a liquid suspension of crystalline or
25 amorphous material with poor water solubility. The rate of absorption of the
drug then depends upon its rate of dissolution which, in turn, may depend upon
crystal size and crystalline form. Alternatively, delayed absorption of a
parenterally administered drug form is accomplished by dissolving or suspending
the drug in an oil vehicle.
30 Injectable depot forms are made by forming microencapsule matrices of
the drug in biodegradable polymers such as polylactide-polyglycolide.
Depending upon the ratio of drug to polymer and the nature of the particular
polymer employed, the rate of drug release can be controlled. Examples of other
biodegradable polymers include poly(orthoesters) and poly(anhydrides) Depot
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injectable formulations are also prepared by entrapping the drug in liposomes or
microemulsions which are compatible with body tissues.
The injectable formulations can be sterilized, for example, by filtration
through a bacterial-retaining filter, or by incorporating sterilizing agents in the
5 form of sterile solid compositions which can be dissolved or dispersed in sterile
water or other sterile injectable medium just prior to use.
Solid dosage forms for oral administration include capsules, tablets, pills,
powders, and granules. In such solid dosage forms, the active compound is
mixed with at least one inert, pharmaceutically acceptable excipient or carrier
10 such as sodium citrate or dicalcium phosphate and/or a) fillers or extenders such
as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such
as, for example, carboxymethylcellulose, alginates, gelatin,
polyvinylpyrrolidone, sucrose, and acacia, c) humectants such as glycerol, d)
disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca
15 starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding
agents such as paraffin, f) absorption accelerators such as quaternary ammonium
compounds, g) wetting agents such as, for example, cetyl alcohol and glycerol
monostearate, h) absorbents such as kaolin and bentonite clay, and i) lubricants
such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols,
20 sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets and
pills, the dosage form may also comprise buffering agents.
Solid compositions of a similar type may also be employed as fillers in
soft and hard-filled gelatin capsules using such excipients as lactose or milk
sugar as well as high molecular weight polyethylene glycols and the like.
25 The solid dosage forms of tablets, dragees, capsules, pills, and granules
can be prepared with coatings and shells such as enteric coatings and other
coatings well known in the pharmaceutical formulating art. They may optionally
contain opacifying agents and can also be of a composition that they release the
active ingredient(s) only, or preferentially, in a certain part of the intestinal tract,
30 optionally, in a delayed manner. Examples of embedding compositions which
can be used include polymeric substances and waxes.
The active compounds can also be in micro-encapsulated form, if
appropriate, with one or more of the above-mentioned excipients.
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Liquid dosage forms for oral administration include pharmaceutically
acceptable emulsions, solutions, suspensions, syrups and elixirs. In addition to
the active compounds, the liquid dosage forms may contain inert diluents
commonly used in the art such as, for example, water or other solvents,
5 solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl
carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-
butylene glycol, dimethyl formamide, oils (in particular, cottonseed, groundnut,
corn, germ, olive, castor, and sesame oils), glycerol, tetrahyarofurfuryl alcohol,
polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.
10 Besides inert diluents, the oral compositions can also include adjuvants
such as wetting agents, emulsifying and suspending agents, sweetening,
flavoring, and perfuming agents.
Suspensions, in addition to the active compounds, may contain
suspending agents as, for example, ethoxylated isostearyl alcohols,
15 polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose,
aluminum metahydroxide, bentonite, agar-agar, and tragacanth, and mixtures
thereof.
Topical administration includes administration to the skin or mucosa,
including surfaces of the lung and eye. Compositions for topical administration,
20 including those for inhalation, may be prepared as a dry powder which may be
pressurized or non-pressurized. In non-pressurized powder compositions, the
active ingredient in finely divided form may be used in admixture with a larger-
sized pharmaceutically acceptable inert carrier comprising particles having a
size, for example, of up to 100 micrometers in diameter. Suitable inert carriers
25 include sugars such as lactose. Desirably, at least 95% by weight of the particles
of the active ingredient have an effective particle size in the range of 0.01 to 10
micrometers.
Alternatively, the composition may be pressurized and contain a
compressed gas, such as nitrogen or a liquified gas propellant. The liquified
30 propellant medium and indeed the total composition is preferably such that the
active ingredient does not dissolve therein to any substantial extent. The
pressurized composition may also contain a surface active agent. ■ The surface
active agent may be a liquid or solid non-ionic surface active agent or may be a
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solid anionic surface active agent. It is preferred to use the solid anionic surface
active agent in the form of a sodium salt.
A further form of topical administration is to the eye, as for the treatment
of immune-mediated conditions of the eye such as automimmue diseases,
5 allergic or inflammatory conditions, and corneal transplants. The compound of
the invention is delivered in a pharmaceutically acceptable ophthalmic vehicle,
such that the compound is maintained in contact with the ocular surface for a
sufficient time period to allow the compound to penetrate the corneal and
internal regions of the eye, as for example the anterior chamber, posterior
10 chamber, vitreous body, aqueous humor, vitreous humor, cornea, iris/cilary, lens,
choroid/retina and sclera. The pharmaceutically acceptable ophthalmic vehicle
may, for example, be an ointment, vegetable oil or an encapsulating material.
Compositions for rectal or vaginal administration are preferably
suppositories which can be prepared by mixing the compounds of this invention
15 with suitable non-irritating excipients or carriers such as cocoa butter,
polyethylene glycol or a suppository wax which are solid at room temperature
but liquid at body temperature and therefore melt in the rectum or vaginal cavity
and release the active compound.
Compounds of the present invention can also be administered in the form
20 of liposomes. As is known in the art, liposomes are generally derived from
phospholipids or other lipid substances. Liposomes are formed by mono- or
multi-lamellar hydrated liquid crystals that are dispersed in an aqueous medium.
Any non-toxic, physiologically acceptable and metabolizable lipid capable of
forming liposomes can be used. The present compositions in liposome form can
25 contain, in addition to a compound of the present invention, stabilizers,
preservatives, excipients, and the like. The preferred lipids are the phospholipids
and the phosphatidyl cholines (lecithins), both natural and synthetic. Methods to
form liposomes are known in the art. See, for example, Prescott, Ed., Methods in
Cell Biology . Volume XIV, Academic Press, New York, N.Y. (1976), p. 33 et
30 seq.
It is understood that the foregoing detailed description and accompanying
examples are merely illustrative and are not to be taken as limitations upon the
scope of the invention, which is defined solely by the appended claims and their
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equivalents. Various changes and modifications to the disclosed embodiments
will be apparent to those skilled in the art. Such changes and modifications,
including without limitation those relating to the chemical structures,
substituents, derivatives, intermediates, syntheses, formulations and/or methods
5 of use of the invention, may be made without departing from the spirit and scope
thereof.
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CLAIMS
What is claimed is:
5
1 . A compound of the formula:
I
10 wherein R 1 is hydrogen, a hydroxy protecting group, loweralkyl or phenyl-
substituted loweralkyl;
R 2 is hydrogen and R 3 is hydroxy or protected hydroxy or R 2 and R 3 taken
together are oxo;
15
R 4 is hydrogen or phenyl-substituted loweralkyl and R 5 is hydroxy or protected
hydroxy or R 5 is hydrogen or phenyl-substituted loweralkyl and R 4 is hydroxy or
protected hydroxy or R 4 and R 5 taken together are oxo;
20 R 6 is hydrogen or phenyl-substituted loweralkyl and R 7 is hydrogen, hydroxy or
protected hydroxy or R 7 is hydrogen or phenyl-substituted loweralkyl and R 6 is
hydroxy or protected hydroxy or R 6 and R 7 taken together are
(1) oxo,
(2) diazo,
25 (3) =CH 2
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(4) -0-(CH 2 ) 2 -0-,
(5) -S-(CH 2 ) 2 -S-,
(6) -0-(CH 2 ) 3 -0-,
(7) -S-(CH 2 ) 3 -S-,
30 (8) =N-OR 20 wherein R 20 is hydrogen, loweralkyl, alkenyl, cycioalkyl,
cycloalkenyl, bicycloalkenyl, aryl, arylalkyl, heterocyclic or
heterocyclicalkyl, each of which is optionally substituted with loweralkyl,
halogen, hydroxy, aryl or heterocyclic; or
(9) =N-N(R2l)(R22) wherein R21 and R 22 are independently selected
35 from hydrogen, loweralkyl, aryl, arylalkyl, heterocyclic and
heterocyclicalkyl;
R 8 is hydrogen;
40 R 9 is
(1) -OS(0) 2 CF 3 ,
(2) -OS(0) 2 F,
(3) -OS(0) 2 R 21 a wherein R 21a is loweralkyl, aryl, arylalkyl, heterocyclic
or heterocyclicalkyl,
45 (4) -OC(0)R 23 wherein R 23 is loweralkyl, cycioalkyl, cycloalkylalkyl,
aryl, arylalkyl, heterocyclic, heterocyclicalkyl, alkoxy, -O-cycloalkyl,
-O-aryl, -O-heterocyclic, -O-(N-succinimidyl) or 5-tetrazolyl;
(5) -OC(0)-N(R 2 4)(R25) wherein R 2 * and R 2 * are independently selected
from
50 (a) hydrogen,
(b) loweralkyl,
(c) alkenyl,
(d) alkynyl,
(e) cycioalkyl,
55 (f) substituted loweralkyl, substituted alkenyl, substituted alkynyl
or substituted cycioalkyl wherein the loweralkyl group, the
alkenyl group, the alkynyl group or the cycioalkyl group is
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substituted by one or two substituents independently selected
from
60 (i) hydroxy,
(ii) -COOH,
(iii) -CN,
(iv) -Q-loweralkyl, -Q-aryl, -Q-(arylalkyl), -Q-
heterocyclic or -Q-(heterocyclicalkyl) wherein Q is -O-,
65 -S-, -S(O)-, -S(0) 2 -, -C(O)-, -OC(O)-, -C(0)0-,
-C(0)C(0)-0-,
-0-C(0)C(0)-, -C(0)NH-, -NHC(O)-, -OC(0)NH-7
-NHC(0)0-, -NH-C(0)-NH-, -S(0) 2 NH-, -NHS(0) 2 -,
-N(R27)_, -C(NR27)NHNH- and -NHNHC(NR27). wherein
70 R 27 is hydrogen, loweralkyl, aryl or heterocyclic,
(v) cycloalkyl,
(vi) aryl,
(vii) heterocyclic,
(viii) -N(R 2 8)(R29) wherein R 28 and R 29 are independently
75 selected from hydrogen, loweralkyl, hydroxyalkyl, aryl
and heterocyclic,
(ix) guanidino,
(x) -S(0) 2 R 11 wherein R 11 is loweralkyl, aryl or arylalkyl,
(xi) -OSCO^R 11 wherein R 11 is defined as above,
80 (xii) -S0 3 H,
(xiii) -S(0) 2 NH 2 ,
(xiv) -SR 28 wherein R 28 is defined as above,
(xv) halogen,
(xvi) oxo and
85 (xvii) epoxy;
(g) aryl,
(h) heterocyclic,
(i) -NHC(0)-0-loweralkyl,
(j) -NHC(0)-aryl,
90 (k) -NHC(Q)-heterocyclic and
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(1) loweralkyl substituted by -OC(0)-R f wherein R f is
carboxyaikyl
or -N(R 24 )(R 25 ) taken together form a nitrogen-containing
heterocyclic group,
95 (6) -OR 25 wherein R 25 is as defined above,
(7) a protected hydroxy group,
(8) -OC(0)N(OR 24 )(R 25 ) wherein R 24 and R 25 are defined as above,
(9) -0(CH 2 )iC{0)OR 20 wherein i is one or two and R 20 is independently
defined as above,
100 (10) -O(CH(Si(CH 3 ) 3 ))-(CH 2 ) j C(O)OR 2 0 wherein j is zero or one "and
R 20 is independently defined as above,
(11) -0(CH 2 ) i C(0)N(R 2 4)(R25) wherein i, R 24 and R25 are defined as
above,
(12) -0(CH 2 ) i C(0)N(OR 24 )(R25 ) wherein i, R 24 and R25 are defined as
105 above,
(13) -0(CH 2 ) i C(0)N(R 24 )(N(R 24 )(R 2 5)) wherein i, R 24 and R25 are
defined as above,
(14) -0(CH 2 ) i NHC(0)N(R 24 )(R 2 5) wherein i, R 24 and R25 are defined as
above,
110 (15) -0(CH 2 ) i NHC(0)N(OR 24 )(R 2 5) wherein i, R24 and R 25 are defined
as above,
(16) -0(CH 2 )jNHC(0)N(R 24 )(N(R 24 )(R 2 5)) wherein i, R24 an d R25 are
defined as above,
(17) -OS(0) 2 N(R 24 )(R 2 5) wherein R 24 and R25 are defined as above,
115 (18) -0(CH 2 ) r NHC(0)R2 4 wherein R24 i s defined as above,
(19) -OCH(R 24 )-SH wherein R 24 is defined as above,
(20) -OCH(R 24 )-S-loweralkyl wherein R 2 4 i s defined as above,
(21) -OCH(R 24 )-S-aryl wherein R24 i s defined as above and
(22) -N 3 ;
120
RlOa i s hydrogen and R 10b is hydrogen, hydroxy, protected hydroxy, alkoxy,
alkenyl, alkenyloxy, halogen or -SR 2 8 wherein R 2 8 i s independendy defined as
above or R 10b is hydrogen and R 10a is hydrogen, hydroxy, protected hydroxy,
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alkoxy, alkenyl, alkenyloxy, halogen or -SR 28 wherein R 28 is independently
125 defined as above or R 10a and R 10b are both alkoxy or -SR 28a wherein R 28a is
loweralkyl, aryl or heterocyclic or R 10a and R 10b taken together are oxo; and
X is hydrogen and Y is hydrogen, hydroxy or protected hydroxy or Y is hydrogen
and X is hydroxy or protected hydroxy or X and Y taken together are oxo;
130
or a pharmaceutically acceptable salt, ester, amide or prodrug thereof.
2. A compound according to Claim 1 wherein
R 1 is methyl;
R 2 is hydrogen and R 3 is hydroxy;
R 4 is hydrogen and R 5 is hydroxy or R 5 is hydrogen and R 4 is hydroxy or R 4 and
5 R 5 taken together are oxo;
R 6 and R 7 are defined as above;
R 8 is hydrogen;
R 9 is defined as above;
RlOa i s hydrogen, methoxy or fluoro and R 10b is hydrogen; and
10 X and Y taken together are oxo.
3. A compound according to Claim 1 wherein
R 1 is methyl;
R 2 is hydrogen and R 3 is hydroxy;
R 4 is hydrogen and R 5 is hydroxy or R 5 is hydrogen and R 4 is hydroxy or R 4 and
5 R 5 taken together are oxo;
R6 and R 7 taken together are
(1) oxo,
(2) =N-OR 20 wherein R 20 is hydrogen, loweralkyl, alkenyl, cycloalkyl,
cycloalkenyl, bicycloalkenyl, aryl, arylalkyl, heterocyclic or
10 heterocyclicalkyl, each of which is optionally substituted with loweralkyl,
halogen, hydroxy, aryl or heterocyclic; or
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(3) =N-N(R21)(R22) wher ei n R 21 and R 22 ^ independently selected
from hydrogen, loweralkyl, aryl, arylalkyl, heterocyclic and
heterocyclicalkyl;
15 R 8 is hydrogen;
R9is
(1) -OH,
(2) -OC(0)R23 wherein R23 i s -O-aryl, -O-(N-succinimidyl), -O-
benzotriazolyl, -0-2'-pyridyl or 5-tetrazolyl,
20 (3) -OC(0)-N(R24) (R 2 5) wherein R24 and R25 are independently selected
from
(a) hydrogen,
(b) loweralkyl,
(c) alkenyl,
25 (d) alkynyl,
(e) cycloalkyl,
(f) substituted loweralkyl, substituted alkenyl, substituted alkynyl
or substituted cycloalkyl wherein the loweralkyl group, the
alkenyl group, the alkynyl group or the cycloalkyl group is
30 substituted by one or two substituents independently selected from
(i) hydroxy,
(ii) -COOH,
(iii) -CN,
(iv) -Q-loweralkyl, -Q-aryl, -Q-(arylalkyl), -Q-heterocyclic
35 or -Q-(heterocyclicalkyl) wherein Q is -O-, -S-, -S(O)-,
-S(0) r , -C(O)-, -OC(O)-, -C(0)0-, -C(0)C(0)-0-,
-0-C(0)C(0)-, -C(0)NH-, -NHC(O)-, -OC(0)NH-,
-NHC(0)0-, -NH-C(0)-NH-, -S(0) 2 NH-, -NHS(0) r ,
-N(R27)., -C(NR27)NHNH- and -NHNHC(NR27 } . whe r e in
40 r27 is hydrogen, loweralkyl, aryl or heterocyclic,
(v) cycloalkyl,
(vi) aryl,
(vii) heterocyclic,
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(viii) -N(R 28 )(R 29 ) wherein R 28 and R 29 are independently
45 selected from hydrogen, loweralkyl, hydroxyalkyl, aryl
and heterocyclic,
(ix) guanidino,
(x) -S(0) 2 R 11 wherein R 11 is loweralkyl, aryl or arylalkyl,
(xi) -OS(0) 2 R 11 wherein R 11 is defined as above,
50 (xii) -S0 3 H,
(xiii) -S(0) 2 NH 2 ,
(xiv) -SR 28 wherein R 28 is defined as above,
(xv) halogen,
(xvi) oxo and
55 (xvii) epoxy;
(g) aryl,
(h) heterocyclic,
(i) -NHC(0)-0-loweralkyl,
(j) -NHC(0)-aryl,
60 (k) -NHC(0)-heterocyclic and
(1) loweralkyl substituted by -OC(0)-R f wherein R f is
carboxyalkyl
or -N(R 24 )(R 25 ) taken together form a nitrogen-containing
heterocyclic group,
65 (4) -OC(0)N(OR 24 )(R 25 ) wherein R 24 and R 25 are defined as above,
(5) -0(CH 2 ) i C(0)N(R 24 )(R 25 ) wherein iis one or two and R 24 and R 25
are defined as above,
(6) -0(CH 2 ) i C(0)N(OR 24 )(R 25 ) wherein i, R 24 and R 2 $ are defined as
above,
70 (7) -0(CH 2 ) i NHC(0)N(R 24 )(R 25 ) wherein i, R 24 and R 2 $ are defined as
above or
(8) -0(CH 2 ) i NHC(0)N(OR 24 )(R 25 ) wherein i, R 24 and R 25 are defined
as above;
RlOa i s hydrogen, methoxy or fluoro and R 10b is hydrogen; and
75 X and Y taken together are oxo.
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4. A compound according to Claim 1 wherein
R 1 is methyl;
R 2 is hydrogen and R 3 is hydroxy;
R 4 and R 5 taken together are oxo;
5 R 6 and R 7 taken together are
(1) oxo,
(2) =N-OR 20 wherein R 20 is hydrogen, loweralkyl, alkenyl, cycloalkyl,
cycloalkenyl, bicycloalkenyl, aryl, arylalkyl, heterocyclic or
heterocyclicalkyl, each of which is optionally substituted with loweralkyl,
10 halogen, hydroxy, aryl or heterocyclic; or
(3) =N-N(R 21 )(R 22 ) wherein R 21 and R 22 are independently selected
from hydrogen, loweralkyl, aryl, arylalkyl, heterocyclic and
heterocyclicalkyl;
R 8 is hydrogen;
15 R9 is
(1) -OH,
(2) -OC(0)R 2 3 wherein R 2 3 is -O-aryl, -O-(N-succinimidyl), -O-
benzotriazolyl, -0-2'-pyridyl or 5-tetrazolyl,
(3) -OC(0)-N(R 24 )(R 2 5) wherein R 24 and R 2 $ are independently selected
20 from
(a) hydrogen,
(b) loweralkyl,
(c) alkenyl,
(d) alkynyl,
25 (e) cycloalkyl,
(f) substituted loweralkyl, substituted alkenyl, substituted alkynyl
or substituted cycloalkyl wherein the loweralkyl group, the
alkenyl group, the alkynyl group or the cycloalkyl group is
substituted by one or two substituents independently selected from
30 (i) hydroxy,
(ii) -COOH,
(iii) -CN,
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(iv) -Q-loweralkyl, -Q-aryl, -Q-(arylaikyl), -Q-heterocyclic
or -Q-(heterocyclicalkyl) wherein Q is -O-, -S-, -S(O)-,
35 -S(0) 2 -, -C(O)-, -OC(O)-, -C(0)0-, -C(0)C(0)-0-,
-0-C(0)C(0)-, -C(0)NH-, -NHC(O)-, -OC(0)NH-,
-NHC(0)0-, -NH-C(0)-NH-, -S(0) 2 NH-, -NHS(0) 2 -,
-N(R27)., -C(NR 2 7)NHNH- and -NHNHCCNR 2 ?)- wherein
R 27 is hydrogen, loweralkyl, aryl or heterocyclic,
40 (v) cycloalkyl,
(vi) aryl,
(vii) heterocyclic,
(viii) -N(R 28 )(R 29 ) wherein R 28 and R 29 are independently
selected from hydrogen, loweralkyl, hydroxyalkyl, aryl
45 and heterocyclic,
(ix) guanidino,
(x) -S(0)2R n wherein R 11 is loweralkyl, aryl or arylalkyl,
(xi) -OS(0) 2 R n wherein R 11 is defined as above,
(xii) -S0 3 H,
50 (xiii) -S(0) 2 NH 2 ,
(xiv) -SR 28 wherein R 28 is defined as above,
(xv) halogen,
(xvi) oxo and
(xvii) epoxy;
55 (g) aryl,
(h) heterocyclic,
(i) -NHC(0)-0-loweralkyl,
(j) -NHC(0)-aryl,
(k) -NHC(0)-heterocyclic and
60 (1) loweralkyl substituted by -OC(0)-R f wherein R f is
carboxyalkyl
or -N(R 24 )(R 25 ) taken together form a nitrogen-containing
heterocyclic group,
(4) -OC(0)N(OR 24 )(R 2 5) wherein R 24 and R 2 5 are defined as above,
65 (5) -0(CH 2 ) i C(0)N(R 24 )(R 2 5) wherein iis one or two and R 24 and R 2 5
are defined as above,
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(6) -0(CH 2 )iC(0)N(OR24)(R25) wh erein i, R24 and R25 are defined as
above,
(7) -0(CH 2 ) i NHC(0)N(R24)( R 25 ) whe rein i, R24 and R25 are defined as
70 above or
(8) -0(CH 2 ) i NHC(0)N(OR24)(R25 ) whe rein i, R24 and R25 ^ defined £
above;
R 10a is methoxy and R 10b is hydrogen; and
X and Y taken together are oxo.
5. A compound according to Claim 1 wherein
R 1 is methyl;
R 2 is hydrogen and R 3 is hydroxy;
R 4 and R 5 taken together are oxo;
5 R 6 and R 7 taken together are oxo;
R 8 is hydrogen;
R 9 is -OH, -O-loweralkyl or -OC(0)N(R24)(R25) wher ein R24 an d r25
defined as above;
R 10a is methoxy and R 10b is hydrogen; and
10 X and Y taken together are oxo.
15
20
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6. A compound of the formula:
II
5 wherein R 1 is hydrogen, a hydroxy protecting group, loweralkyl or phenyl-
substituted loweralkyl;
R 2 is hydrogen and R 3 is hydroxy or protected hydroxy or R 2 and R 3 taken
together are oxo;
10
R 4 is hydrogen or phenyl-substituted loweralkyl and R 5 is hydroxy or protected
hydroxy or R 5 is hydrogen or phenyl-substituted loweralkyl and R 4 is hydroxy or
protected hydroxy or R 4 and R 5 taken together are oxo;
15 R 6 is hydrogen or phenyl-substituted loweralkyl and R 7 is hydrogen, hydroxy or
protected hydroxy or R 7 is hydrogen or phenyl-substituted loweralkyl and R 6 is
hydroxy or protected hydroxy or R 6 and R 7 taken together are
(1) oxo,
(2) diazo,
20 (3)=CH 2
(4) -0-(CH 2 ) 2 -0-,
(5) -S-(CH 2 ) 2 -S-,
(6) -0-(CH 2 ) 3 -0-,
(7) -S-(CH 2 ) 3 -S-,
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25 (8) =N-OR 2 0 wherein R 2 0 is hydrogen, loweralkyl, alkenyl, cycloalkyl,
cycloalkenyl, bicycloalkenyl, aryl, arylalkyl, heterocyclic or
heterocyclicalkyl, each of which is optionally substituted with loweralkyl,
halogen, hydroxy, aryl or heterocyclic; or
(9) =N-N(R2l)(R22) wherein R21 and R22 are independently selected
30 from hydrogen, loweralkyl, aryl, arylalkyl, heterocyclic and
heterocyclicalkyl;
R 8 is hydrogen;
35 R9 is
(1) -SR24 wherein R24 i s
(a) hydrogen,
(b) loweralkyl,
(c) alkenyl,
4 0 (d) alkynyl,
(e) cycloalkyl,
(f) substituted loweralkyl, substituted alkenyl, substituted alkynyl
or substituted cycloalkyl wherein the loweralkyl group, the
alkenyl group, the alkynyl group or the cycloalkyl group is
45 substituted by one or two substituents independently selected from
(i) hydroxy,
(ii) -COOH,
(iii) -CN,
(iv) -Q-loweralkyl, -Q-aryl, -Q-(arylalkyl), -Q-heterocyclic
50 or -Q-(heterocyclicalkyl) wherein Q is -O-, -S-, -S(O)-,
-S(0) 2 -, -C(O)-, -OC(O)-, -C(0)0-, -C(0)C(0)-0-,
-0-C(0)C(0)-, -C(0)NH-, -NHC(O)-, -OC(0)NH-,
-NHC(0)0-, -NH-C(0)-NH-, -S(0) 2 NH-, -NHS(0) r ,
-N(R27 K -C(NR27)NHNH- and -NHNHC(NR27). whe rein
55 * r27 is hydrogen, loweralkyl, aryl or heterocyclic,
(v) cycloalkyl,
(vi) aryl,
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(vii) heterocyclic,
(viii) -N(R 28 )(R 29 ) wherein R 28 and R 29 are independently
60 selected from hydrogen, loweralkyl, hydroxyalkyl, aryl
and heterocyclic,
(ix) guanidino,
(x) -S(0) 2 R 11 wherein R 11 is loweralkyl, aryl or arylalkyl,
(xi) -OS(0) 2 R 11 wherein R 11 is defined as above,
65 (xii) -S0 3 H,
(xiii) -S(0) 2 NH 2 ,
(xiv) -SR 28 wherein R 28 is defined as above,
(xv) halogen,
(xvi) oxo and
70 (xvii) epoxy;
(g) aryl,
(h) heterocyclic,
(i) -C(0)-0-loweralkyl,
(j)-C(0)-aryl,
75 (k) -C(0)-heterocyclic or
(1) loweralkyl substituted by -OC(0)-R f wherein R f is
carboxyalkyl,
(2) -SC(=NH)-NH 2 ,
(3) -SC(=N-NH 2 )-NH 2 ,
80 (4) -Se-phenyl or
(5) -Se(0)-phenyl;
RlOa i s hydrogen and R 10b is hydrogen, hydroxy, protected hydroxy, alkoxy,
alkenyl, alkenyloxy, halogen or -SR 28 wherein R 28 is independently defined as
above or R 10b is hydrogen and R 10a is hydrogen, hydroxy, protected hydroxy,
85 alkoxy, alkenyl, alkenyloxy, halogen or -SR 28 wherein R 28 is independently
defined as above or R 10a and R 10b are both alkoxy or -SR 28a wherein R 28a is /
loweralkyl, aryl or heterocyclic or R 10a and R 10b taken together are oxo; and
X is hydrogen and Y is hydrogen, hydroxy or protected hydroxy or Y is hydrogen
and X is hydroxy or protected hydroxy or X and Y taken togehter are oxo;
90
or a pharmaceutically acceptable salt, ester, amide or prodrug thereof.
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7. A compound according to Claim 6 wherein
R 1 is methyl;
R 2 is hydrogen and R 3 is hydroxy;
R 4 is hydrogen and R 5 is hydroxy or R 5 is hydrogen and R 4 is hydroxy or R 4 and
5 R 5 taken together are oxo;
R 6 and R 7 are defined as above;
R 8 is hydrogen;
R9 is -SR 24 wherein R 24 is defined as above;
RlOa i s hydrogen, methoxy or fluoro and R 10b is hydrogen; and
10 X and Y taken together are oxo.
8. A compound according to Claim 6 wherein
R 1 is methyl;
R 2 is hydrogen and R 3 is hydroxy;
R 4 is hydrogen and R 5 is hydroxy or R 5 is hydrogen and R 4 is hydroxy or R 4 and
5 R 5 taken together are oxo;
R 6 and R 7 taken together are
(1) oxo,
(2) =N-OR 20 wherein R 20 is hydrogen, loweralkyl, alkenyl, cycloalkyl,
cycloalkenyl, bicycloalkenyl, aryl, arylalkyl, heterocyclic or
10 heterocyclicalkyl, each of which is optionally substituted with loweralkyl,
halogen, hydroxy, aryl or heterocyclic; or
(3) =N-N(R 2 *)(R 22 ) wherein R 2 * and R 22 are independently selected
from hydrogen, loweralkyl, aryl, arylalkyl, heterocyclic and
heterocyclicalkyl;
15 R 8 is hydrogen;
R 9 is -SR 24 wherein R 24 is hydrogen, loweralkyl, substituted loweralkyl as
defined above, aryl or heterocyclic;
RlOa i s hydrogen, methoxy or fluoro and R 10b is hydrogen; and
X and Y taken together are oxo.
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9. A compound according to Claim 6 wherein
R 1 is methyl;
R 2 is hydrogen and R 3 is hydroxy;
5 R 4 and R 5 taken together are oxo;
R 6 and R 7 taken together are oxo;
R 8 is hydrogen;
R 9 is -SR 24 wherein R 24 is hydrogen, loweralkyl, substituted loweralkyl as
defined above, aryl or heterocyclic;
10 R 10a is methoxy and R 10b is hydrogen; and
X and Y taken together are oxo.
10. A compound according to Claim 6 wherein
R 1 is methyl;
R 2 is hydrogen and R 3 is hydroxy;
R 4 and R 5 taken together are oxo;
5 R 6 and R 7 taken together are oxo;
R 8 is hydrogen;
R 9 is -SR 24 wherein R 24 is hydrogen, imidazol-2-yl or N-methyl-imidazol-2-yl;
R 10a is methoxy and R 10b is hydrogen; and
X and Y taken together are oxo.
20
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11. A compound of the formula:
CH3O*'
m
10
15
20
wherein R 1 is hydrogen, a hydroxy protecting group, loweralkyl or phenyl-
substituted loweralkyl;
R 2 is hydrogen and R 3 is hydroxy or protected hydroxy or R 2 and R 3 taken
together are oxo;
R 4 is hydrogen or phenyl-substituted loweralkyl and R 5 is hydroxy or protected
hydroxy or R 5 is hydrogen or phenyl-substituted loweralkyl and R 4 is hydroxy or
protected hydroxy or R 4 and R 5 taken together are oxo;
R 6 is hydrogen or phenyl-substituted loweralkyl and R 7 is hydrogen, hydroxy or
protected hydroxy or R 7 is hydrogen or phenyl-substituted loweralkyl and R 6 is
hydroxy or protected hydroxy or R 6 and R 7 taken together are
(1) oxo,
(2) diazo,
(3) =CH 2
(4) -0-(CH 2 ) 2 -0-,
(5) -S-(CH 2 ) 2 -S-,
(6) -0-(CH 2 ) 3 -0-,
(7) -S-(CH 2 ) 3 -S-,
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25 (8) =N-OR 20 wherein R 20 is hydrogen, loweralkyl, alkenyl, cycloalkyl,
cycloalkenyl, bicycloalkenyl, aryl, arylalkyl, heterocyclic or
heterocyclicalkyl, each of which is optionally substituted with loweralkyl,
halogen, hydroxy, aryl or heterocyclic; or
(9) =N-N(R 21 )(R 22 ) wherein R 21 and R 22 are independently selected
30 from hydrogen, loweralkyl, aryl, arylalkyl, heterocyclic and
heterocyclicalkyl;
R8 is hydrogen;
35 R 9 is
(1) -N(R 24 )(R 25 ) wherein R 24 and R 25 are independentiy selected from
(a) hydrogen,
(b) loweralkyl,
(c) alkenyl,
40 (d) alkynyl,
(e) cycloalkyl,
(f) substituted loweralkyl, substituted alkenyl, substituted alkynyl
or substituted cycloalkyl wherein the loweralkyl group, the
alkenyl group, the alkynyl group or the cycloalkyl group is
45 substituted by one or two substituents independently selected from
(i) hydroxy,
(ii) -COOH,
(iii) -CN,
(iv) -Q-loweralkyl, -Q-aryl, -Q-(arylalkyl), -Q-heterocyclic
50 or -Q-(heterocyclicalkyl) wherein Q is -O-, -S-, -S(O)-,
-S(0) 2 -, -C(O)-, -OC(O)-, -C(0)0-, -C(0)C(0)-0-,
-0-C(0)C(0)-, -C(0)NH-, -NHC(O)-, -OC(0)NH-,
-NHC(0)0-, -NH-C(0)-NH-, -S(0) 2 NH-, -NHS(0) 2 -,
-N(R 27 )-, -C(NR 27 )NHNH- and -NHNHC(NR 27 )- wherein
55 R 27 is hydrogen, loweralkyl, aryl or heterocyclic,
(v) cycloalkyl,
(vi) aryl,
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(vii) heterocyclic,
(viii) -N(R 2 8)(R 2 9) wherein R 28 and R 29 are independently
60 selected from hydrogen, loweralkyl, hydroxyalkyl, aryl
and heterocyclic,
(ix) guanidino,
(x) -S(0) 2 R 11 wherein R 11 is loweralkyl, aryl or arylalkyl,
(xi) -OS(0) 2 R n wherein RH is defined as above,
65 (xii) -S0 3 H,
(xiii) -S(0) 2 NH 2 ,
(xiv) -SR 28 wherein R 28 is defined as above,
(xv) halogen,
(xvi) oxo and
70 (xvii) epoxy;
(g) aryl,
(h) heterocyclic,
(i) -NHC(0)-0-loweralkyl,
(j) -NHC(0)-aryl,
75 (k) -NHC(0)-heterocyclic and
(1) loweralkyl substituted by -OC(0)-R f wherein R f is
carboxyalkyl,
(2) -N=C=0,
(3) -NHC(0)-R* or
80 (4) -NHS(0) 2 -R* wherein R* is
(a) loweralkyl,
(b) cycloalkyl,
(c) aryl,
(d) heterocyclic,
8 5 (e) loweralkyl substituted by one or two substituents
independently selected from
(i) hydroxy,
(ii) -COOH,
(iii) -CN,
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90 (iv) -Q-loweralkyl, -Q-axyl, -Q-(arylalkyl), -Q-heterocyclic
or -Q-(heterocyclicalkyl) wherein Q is -O-, -S-, -S(O)-,
-S(0) 2 -, -C(O)-, -OC(O)-, -C(0)0-, -C(0)C(0)-0-,
-0-C(0)C(0)-, -C(0)NH-, -NHC(O)-, -OC(0)NH-,
-NHC(0)0-, -NH-C(0)-NH-, -S(0) 2 NH-, -NHS(0) r ,
95 -N(R 27 )-, -C(NR 27 )NHNH- and -NHNHC(NR 27 )- wherein
R 27 is hydrogen, loweralkyl, aryl or heterocyclic,
(v) cycloalkyl,
(vi) aryl,
(vii) heterocyclic,
100 (viii) -N(R 28 )(R 29 ) wherein R 28 and R 29 are independently
selected from hydrogen, loweralkyl, hydroxyalkyl, aryl
and heterocyclic,
(ix) guanidino,
(x) -S(0) 2 R 11 wherein R 11 is loweralkyl, aryl or arylalkyl,
105 (xi) -OS(0) 2 R! 1 wherein R 11 is defined as above,
(xii) -S0 3 H,
(xiii) -S(0) 2 NH 2 ,
(xiv) -SR 28 wherein R 28 is defined as above,
(xv) halogen,
110 (xvi) oxo and
(xvii) epoxy;
(f) -N(R a )(R b ) wherein R a and R b are independently selected from
hydrogen, loweralkyl and -N(R c )(R d ) wherein R c and R d are
independently selected from hydrogen and loweralkyl or
1 15 (g) -OR* wherein R* is defined as above;
RlOa i s hydrogen and R 10b is hydrogen, hydroxy, protected hydroxy, alkoxy,
alkenyl, alkenyloxy, halogen or -SR 28 wherein R 28 is independently defined as
above or R 10b is hydrogen and R 10a is hydrogen, hydroxy, protected hydroxy,
120 alkoxy, alkenyl, alkenyloxy, halogen or -SR 28 wherein R 28 is independently
defined as above or R 10a and R 10b are both alkoxy or -SR 28a wherein R 28a is
loweralkyl, aryl or heterocyclic or R 10a and R 10b taken together are oxo; and
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X is hydrogen and Y is hydrogen, hydroxy or protected hydroxy or Y is hydrogen
125 and X is hydroxy or protected hydroxy or X and Y taken togehter are oxo;
or a pharmaceutically acceptable salt, ester, amide or prodrug thereof.
12. A compound according to Claim 11 wherein
R 1 is methyl;
R 2 is hydrogen and R3 is hydroxy;
5 R 4 is hydrogen and R 5 is hydroxy or R 5 is hydrogen and R 4 is hydroxy or R 4 and
R 5 taken together are oxo;
R 6 and R 7 are defined as above;
R 8 is hydrogen;
R 9 is -N(R24)(R25) wherein R 24 and R 2 5 are defined as above;
10 R 10a is hydrogen, methoxy or fluoro and R 10b is hydrogen; and
X and Y taken together are oxo.
13. A compound according to Claim 1 1 wherein
R 1 is methyl;
R 2 is hydrogen and R 3 is hydroxy;
R 4 is hydrogen and R 5 is hydroxy or R5 is hydrogen and R 4 is hydroxy or R 4 and
5 R 5 taken together are oxo;
R 6 and R 7 taken together are
(1) oxo,
(2) =N-OR 20 wherein R 2 0 is hydrogen, loweralkyl, alkenyl, cycloalkyl,
cycloalkenyl, bicycloalkenyl, aryl, arylalkyl, heterocyclic or
10 heterocyclicalkyl, each of which is optionally substituted with loweralkyl,
halogen, hydroxy, aryl or heterocyclic; or
(3) =N-N(R 21 )(R 22 ) wherein R 21 and R 22 are independently selected
from hydrogen, loweralkyl, aryl, arylalkyl, heterocyclic and
heterocyclicalkyl;
15 R 8 is hydrogen;
R 9 is -N(R 24 )(R 25 ) wherein R 24 and R 25 are independently selected from
hydrogen, loweralkyl, substituted loweralkyl as defined above.
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-NHC(0)-0-loweralkyl, -NHC(0)-aryl and -NHC(0)-heterocyclic or R 24 and
R.25 taken together form a heterocyclic ring;
20 R 10a is hydrogen, methoxy or fluoro and R 10b is hydrogen; and
X and Y taken together are oxo.
14. A compound according to Claim 1 1 wherein
R 1 is methyl;
R 2 is hydrogen and R 3 is hydroxy;
R 4 and R 5 taken together are oxo;
5 R 6 and R 7 taken together are oxo;
R8 is hydrogen;
R 9 is -N(R 24 )(R 25 ) wherein R 24 and R 25 are independently selected from
hydrogen, loweralkyl, substituted loweralkyl as defined above,
-NHC(0)-0-loweralkyl„ -NHC(0)-aryl and -NHC(0)-heterocyclic or R 24 and
10 R 25 taken together form a heterocyclic ring;
R 10a is methoxy and R 10b is hydrogen; and
X and Y taken together are oxo.
15. A compound according to Claim 1 1 wherein
R 1 is methyl;
R 2 is hydrogen and R 3 is hydroxy;
R 4 and R 5 taken together are oxo;
5 R 6 and R 7 taken together are oxo;
R 8 is hydrogen;
R 9 is -NH 2 , 2-pyridon-l-yl or 4-pyridon-l-yl;
R 10a is methoxy and R 10b is hydrogen; and
X and Y taken together are oxo.
10
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20 R 1 is hydrogen, a hydroxy protecting group, loweralkyl or phenyl-substituted
loweralkyl;
R 2 is hydrogen and R 3 is hydroxy or protected hydroxy or R 2 and R 3 taken
together are oxo;
R 4 is hydrogen or phenyl-substituted loweralkyl and R 5 is hydroxy or protected
hydroxy or R5 is hydrogen or phenyl-substituted loweralkyl and R 4 is hydroxy or
protected hydroxy or R 4 and R 5 taken together are oxo;
R 6 is hydrogen or phenyl-substituted loweralkyl and R 7 is hydrogen, hydroxy or
protected hydroxy or R 7 is hydrogen or phenyl-substituted loweralkyl and R 6 is
hydroxy or protected hydroxy or R 6 and R 7 taken together are
(1) oxo,
(2) diazo,
(3) =CH 2
(4) -O-(CH 2 ) 2 -0-,
(5) -S-(CH 2 ) 2 -S-,
(6) -0-(CH 2 ) 3 -0-,
(7) -S-(CH 2 ) 3 -S-,
(8) =N-OR 20 wherein R 2 0 is hydrogen, loweralkyl, alkenyl, cycloalkyl,
cycloalkenyl, bicycloalkenyl, aryl, arylalkyl, heterocyclic or
heterocyclicalkyl, each of which is optionally substituted with loweralkyl,
halogen, hydroxy, aryl or heterocyclic; or
(9) =N-N(R 21 )(R 22 ) wherein R 21 and R 22 are independently selected
from hydrogen, loweralkyl, aryl, arylalkyl, heterocyclic and
heterocyclicalkyl;
R 8 , R 9 , R 18 and R 19 are independently selected from
(1) hydrogen,
50 (2) -OS(0) 2 CF 3 ,
(3) -OS(0) 2 F,
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(4) -OS(0) 2 R 21a wherein R 21a is loweralkyl, aryl, arylalkyl, heterocyclic
or heterocyclicalkyl,
(5) -OC(0)R 2 3 wherein R23 i s -O-aryl, -O-(N-succinimidyl),
55 -O-benzotriazolyl, -0-2'-pyridyl or 5-tetrazolyl;
(6) -OC(0)-N(R24)(R25) wherein R24 and R25 are independently selected
from
(a) hydrogen,
(b) loweralkyl,
60 ( C ) alkenyl,
(d) alkynyl,
(e) cycloalkyl,
(f) substituted loweralkyl, substituted alkenyl, substituted alkynyl
or substituted cycloalkyl wherein the loweralkyl group, the
65 alkenyl group, the alkynyl group or the cycloalkyl group is
substituted by one or two substituents independently selected from
(i) hydroxy,
(ii) -COOH,
(iii) -CN,
70 (iv) -Q-loweralkyl, -Q-aryl, -Q-(arylalkyl), -Q-heterocyclic
or -Q-(heterocyclicalkyl) wherein Q is -O-, -S-, -S(O)-,
-S(0) 2 -, -C(O)-, -OC(O)-, -C(0)0-, -C(0)C(0)-0-,
-0-C(0)C(0)-, -C(0)NH-, -NHC(O)-, -OC(0)NH-,
-NHC(0)0-, -NH-C(0)-NH-, -S(0) 2 NH-, -NHS(0) 2 -,
75 -N(R27)_, -C(NR27)NHNH- and -NHNHC(NR27). wherein
R 27 is hydrogen, loweralkyl, aryl or heterocyclic,
(v) cycloalkyl,
(vi) aryl,
(vii) heterocyclic,
(viii) -N(R28)( R 29) wherein R 2 « and R 2 9 are independently
selected from hydrogen, loweralkyl, hydroxyalkyl, aryl
and heterocyclic,
(ix) guanidino,
(x) -S(0) 2 R n wherein R 11 is loweralkyl, aryl or arylalkyl,
80
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85 (xi) -OS(0) 2 R n wherein R 11 is defined as above,
(xii) -S0 3 H,
(xiii) -S(0) 2 NH 2 ,
(xiv) -SR 28 wherein R 28 is defined as above,
(xv) halogen,
90 (xvi) oxo and
(xvii) epoxy;
(g) aryl,
(h) heterocyclic,
(i) -NHC(0)-0-loweralkyl,
95 (j) -NHC(0)-aryl,
(k) -NHC(0)-heterocyclic and
(1) loweralkyl substituted by -OC(0)-R f wherein R f is
carboxyalkyl
or -N(R 24 )(R 2 -0 taken together form a nitrogen-containing
100 heterocyclic group,
(7) -OR 2 ^ wherein R 2 ^ is as defined above,
(8) a protected hydroxy group,
(9) -OC(0)N(OR 24 )(R 25 ) wherein R 24 and R 25 are defined as above,
(10) -0(CH 2 )jC(0)OR 20 wherein i is one or two and R 20 is independently
105 defined as above,
(11) -O(CH(Si(CH 3 ) 3 ))-(CH 2 )jC(O)OR 2 0 wherein j is zero or one and
R 2 0 is independently defined as above,
(12) -0(CH 2 )iC(0)N(R 24 )(R 2 5) wherein i, R 24 and R 25 are defined as
above,
1 10 (13) -0(CH 2 )jC(0)N(OR 24 )(R 25 ) wherein i, R 24 and R 25 are defined as
above,
(14) -0(CH 2 ) i C(0)N(R 24 )(N(R 24 )(R 2 5)) wherein i, R 24 and R 25 are
defined as above,
(15) -0(CH 2 ) i NHC(0)N(R 24 )(R 2 5) wherein i, R 24 and R 25 are defined as
115 above,
(16) -0(CH 2 ) i NHC(0)N(OR 24 )(R 2 5) wherein i, R 24 and R 2 $ are defined
as above,
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(17) -0(CH 2 ) i NHC(0)N(R24)(N(R24)( R 25 )) wher ein i, R24 and R25 are
defined as above,
120 (18) -OS(0) 2 N(R24)(R25) whe rein R24 and R25 axe defined as above,
(19) -0(CH 2 ) r NHC(0)R24 wherein R24 i s defined as above,
(20) -OCH(R24)-SH wherein R24 i s defined as above,
(21) -OCH(R24)-S-loweralkyl wherein R24 i s defined as above,
(22) -OCH(R24)-S-aryl wherein R24 i s defined as above,
125 (23) -N 3 ,
(24) -N=C=0,
(25) -N(R24)(R25) wherein R24 an d R25 are defined as above,
(26) -NHC(0)-R24 wherein R24 i s defined as above,
(27) -NHC(0)-N(R24)(R25) whe rein R24 an d R25 are defined as above,
1 30 (28) -S-R24 wherein R24 i s defined as above and
(29) -S-q-R24 wherein q is a divalent radical selected from the group
consisting of -S-, -C(O)-, -C(0)-0-, -C(0)-NH- and -C(N(R27))-NHNH-
and R24 and R27 are defined as above,
with the proviso that one of R 8 and R 9 is hydrogen and the other is not
135 hydrogen and one of Rl8 and Rl9 is hydrogen and the other is not
hydrogen; or
R 8 and R 9 taken together are
(1) oxo,
(2) =N-0-R24 wherein R 2 4 i s defined as above or
140 (3) =N-N(R24 )( R25) wherein R 24 and R 25 are defined as above; or
R 18 and R 19 taken together are
(1) oxo,
(2) =N-0-R24 wherein R24 i s independently defined as above or
(3) =N-N(R24)(R25) wherein R24 an d R25 are independently defined as
145 above; or
one of R 8 and R 9 taken together with one of R 18 and R 19 form a heterocyclic ring
with the others of R 8 , R 9 , R* 8 and R 19 being hydrogen or together forming a
bond; or
R 8 and R* 8 are hydrogen and R 8 ' and R 19 form a bond;
150
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RlOa i s hydrogen and R 10b is hydrogen, hydroxy, protected hydroxy, alkoxy,
alkenyl, alkenyloxy, halogen or -SR 28 wherein R 28 is independently defined as
above or R 10b is hydrogen and R 10a is hydrogen, hydroxy, protected hydroxy,
alkoxy, alkenyl, alkenyloxy, halogen or -SR 28 wherein R 28 is independently
155 defined as above or R 10a and R 10b are both alkoxy or -SR 28a wherein R 28a is
loweralkyl, aryl or heterocyclic or R 10a and R 10b taken together are oxo; and
X is hydrogen and Y is hydrogen, hydroxy or protected hydroxy or Y is hydrogen
and X is hydroxy or protected hydroxy or X and Y taken togehter are oxo;
160
or a pharmaceutically acceptable salt, ester, amide or prodrug thereof.
17. A compound according to Claim 16 wherein
Z is
5
R 1 is methyl;
10 R 2 is hydrogen and R 3 is hydroxy;
R 4 is hydrogen and R 5 is hydroxy or R 5 is hydrogen and R 4 is hydroxy or R 4 and
R 5 taken together are oxo;
R 6 and R 7 are defined as above;
R 10a is hydrogen, methoxy or fluoro and R 10b is hydrogen; and
15 X and Y taken together are oxo.
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18. A compound according to Claim 16 wherein
Z is
5
R 1 is methyl;
R 2 is hydrogen and R 3 is hydroxy;
R 4 is hydrogen and R 5 is hydroxy or R 5 is hydrogen and R 4 is hydroxy or R 4 and
R 5 taken together are oxo;
R 6 and R 7 taken together are
(1) oxo,
(2) =N-OR 20 wherein R 20 is hydrogen, loweralkyl, alkenyl, cycloalkyl,
cycloalkenyl, bicycloalkenyl, aryl, arylalkyl, heterocyclic or
heterocyclicalkyl, each of which is optionally substituted with loweralkyl,
halogen, hydroxy, aryl or heterocyclic; or
(3) =N-N(R 21 )(R 22 ) wherein R 21 and R 22 are independendy selected
from hydrogen, loweralkyl, aryl, arylalkyl, heterocyclic and
heterocyclicalkyl;
RlOa i s hydrogen, methoxy or fluoro and R 10b is hydrogen; and
X and Y taken together are oxo.
15
20
25
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19. A compound according to Claim 16 wherein
Zis
5
(O °
H
10 R 1 is methyl;
R 2 is hydrogen and R 3 is hydroxy;
R 4 and R 5 taken together are oxo;
R 6 and R 7 taken together are
(1) oxo,
15 (2) =N-OR 20 wherein R 20 is hydrogen, loweralkyl, alkenyl, cycloalkyl,
cycloalkenyl, bicycloalkenyl, aryl, arylalkyl, heterocyclic or
heterocyclicalkyl, each of which is optionally substituted with loweralkyl,
halogen, hydroxy, aryl or heterocyclic; or
(3) =N-N(R 21 )(R 22 ) wherein R 21 and R 22 are independently selected
20 from hydrogen, loweralkyl, aryl, arylalkyl, heterocyclic and
heterocyclicalkyl;
R 10a is methoxy and R 10b is hydrogen; and
X and Y taken together are oxo.
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20. A compound according to Claim 16 wherein
Zis
5
10 R 1 is methyl;
R 2 is hydrogen and R 3 is hydroxy;
R 4 and R 5 taken together are oxo;
R 6 and R 7 taken together are oxo;
R 10a is methoxy and R 10b is hydrogen; and
15 X and Y taken together are oxo.
25
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21. A compound of the formula:
10
15
R 2 is hydrogen and R3 is hydroxy or protected hydroxy or R2 and R3 taken
together are oxo;
R 4 is hydrogen or phenyl-substituted loweraLkyl and R5 is hydroxy or protected
hydroxy or R5 i s hydrogen or phenyl-substituted loweralkyl and R 4 is hydroxy or
protected hydroxy or R 4 and R 5 taken together are oxo;
R 6 is hydrogen or phenyl-substituted loweralkyl and R? is hydrogen, hydroxy or
protected hydroxy or R? is hydrogen or phenyl-substituted loweralkyl and R6 is
hydroxy or protected hydroxy or R<5 and R? taken together are
(1) oxo,
(2) diazo,
20 (3) =CH 2
(4) -0-(CH 2 ) 2 -0-,
(5) -S-(CH 2 ) 2 -S-,
(6) -0-(CH 2 ) 3 -0-,
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25 (7) -S-(CH 2 ) 3 -S-,
( (8) =N-OR 20 wherein R 20 is hydrogen, loweralkyl, alkenyl, cycloalkyl,
cycloalkenyl, bicycloalkenyl, aryl, arylalkyl, heterocyclic or
j heterocyclicalkyl, each of which is optionally substituted with loweralkyl,
halogen, hydroxy, aryl or heterocyclic; or
30 (9) =N-N(R 21 )(R 22 ) wherein R 21 and R 22 are independently selected
from hydrogen, loweralkyl, aryl, arylalkyl, heterocyclic and
heterocyclicalkyl;
R«is
35 (1) -OC(O)N(OR 20 )(R 24 ) or
(2) -0-C(0)-NHN(R 2 4)(R 2 5)
wherein R 20 is hydrogen, loweralkyl, alkenyl, cycloalkyl, cycloalkenyl,
bicycloalkenyl, aryl or heterocyclic, each of which is optionally
substituted with loweralkyl, hydroxy, aryl or heterocyclic and R 24 and
40 R 25 are independently selected from
(a) hydrogen,
(b) loweralkyl,
(c) alkenyl,
(d) alkynyl,
45 (e) cycloalkyl,
(f) substituted loweralkyl, substituted alkenyl, substituted alkynyl
or substituted cycloalkyl wherein the loweralkyl group, the
alkenyl group, the alkynyl group or the cycloalkyl group is
substituted by one or two substituents independently selected from
50 (i) hydroxy,
(ii) -COOH,
(iii) -CN,
(iv) -Q-loweralkyl, -Q-aryl, -Q-(arylalkyl), -Q-heterocyclic
or -Q-(heterocyclicalkyl) wherein Q is -O-, -S-, -S(O)-,
55 -S(0) r , -C(O)-, -OC(O)-, -C(0)0-, -C(0)C(0)-0-,
-0-C(0)C(0)-, -C(0)NH-, -NHC(O)-, -OC(0)NH-,
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-NHC(0)0-, -NH.-C(0)-NH-, -S(0) 2 NH-, -NHS(0) 2 -,
-N(R 27 )-, -C(NR 27 )NHNH- and -NHNHC(NR 27 )- wherein
R 27 is hydrogen, loweralkyl, aryl or heterocyclic,
60 (v) cycloalkyl,
(vi) aryl,
(vii) heterocyclic,
(viii) -N(R 28 )(R 29 ) wherein R 28 and R 29 are independently
selected from hydrogen, loweralkyl, hydroxyalkyl, aryl
65 and heterocyclic,
(ix) guanidino,
(x) -S(0) 2 R 11 wherein R 11 is loweralkyl, aryl or arylalkyl,
(xi) -OS(0) 2 R n wherein R 11 is defined as above,
(xii) -S0 3 H,
70 (xiii) -S(0) 2 NH 2 ,
(xiv) -SR 28 wherein R 28 is defined as above,
(xv) halogen,
(xvi) oxo and
(xvii) epoxy;
75 (g) aryl,
(h) heterocyclic,
(i) -NHC(0)-0-loweralkyl,
0) -NHC(0)-aryl,
(k) -NHC(0)-heterocyclic or
80 (1) loweralkyl substituted by -OC(0)-R f wherein R f is
carboxyalkyl
or -N(R 24 )(R 25 ) taken together form a nitrogen-containing
heterocyclic group;
85 R 9 is hydrogen;
RlOa i s hydrogen and R 10b is hydrogen, hydroxy, protected hydroxy, alkoxy,
alkenyl, alkenyloxy, halogen or -SR 28 wherein R 28 is independently defined as
above or R 10b is hydrogen and R 10a is hydrogen, hydroxy, protected hydroxy,
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90 alkoxy, alkenyl, alkenyloxy, halogen or -SR 28 wherein R 28 is independently
defined as above or R 10a and R 10b are both alkoxy or -SR 28a wherein R 28a is
loweralkyl, aryl or heterocyclic or R 1 ^ and R 10t) taken together are oxo; and
X is hydrogen and Y is hydrogen, hydroxy or protected hydroxy or Y is hydrogen
95 and X is hydroxy or protected hydroxy or X and Y taken togehter are oxo;
or a pharmaceutically acceptable salt, ester, amide or prodrug thereof.
22. A compound according to Claim 21 wherein
R 1 is methyl;
R 2 is hydrogen and R 3 is hydroxy;
R 4 is hydrogen and R 5 is hydroxy or R 5 is hydrogen and R 4 is hydroxy or R 4 and
5 R 5 taken together are oxo;
R 6 and R 7 are defined as above;
R 8 is defined as above;
R 9 is hydrogen;
RlOa j s hydrogen, methoxy or fluoro and R 10b is hydrogen;
10 R 20 is defined as above;
R 24 is defined as above; and
X and Y taken together are oxo.
23. A compound according to Claim 21 wherein
R 1 is methyl;
R 2 is hydrogen and R 3 is hydroxy;
R 4 is hydrogen and R 5 is hydroxy or R 5 is hydrogen and R 4 is hydroxy or R 4 and
5 R5 taken together are oxo;
R6 and R 7 taken together are
(1) oxo,
(2) =N-OR 20 wherein R 20 is hydrogen, loweralkyl, alkenyl, cycloalkyl,
cycloalkenyl, bicycloalkenyl, aryl, arylalkyl, heterocyclic or
10 heterocyclicalkyl, each of which is optionally substituted with loweralkyl,
halogen, hydroxy, aryl or heterocyclic; or
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(3) =N-N(R 21 )(R 22 ) wherein R 21 and R 22 are independently selected
from hydrogen, loweralkyl, aryl, arylalkyl, heterocyclic and
heterocyclicalkyl;
15 R 8 is -OC(O)N(OR 20 )(R 24 ) wherein R 20 and R 24 are defined as above;
RlOa i s hydrogen, methoxy or fluoro and R 10b is hydrogen; and
X and Y taken together are oxo.
24. A compound according to Claim 21 wherein
R 1 is methyl;
R 2 is hydrogen and R 3 is hydroxy;
R 4 and R 5 taken together are oxo;
5 R 6 and R 7 taken together are oxo;
R 8 is -OC(O)N(OR 20 )(R 24 ) wherein R 20 is hydrogen, loweralkyl or arylalkyl and
R 24 is hydrogen, loweralkyl or cycloalkyl;
R 10a is methoxy and R 10b is hydrogen; and
X and Y taken together are oxo.
10
25. A compound according to Claim 21 wherein
R 1 is methyl;
R 2 is hydrogen and R 3 is hydroxy;
R 4 and R 5 taken together are oxo;
5 R 6 and R 7 taken together are oxo;
R 8 is -OC(O)N(OR 20 )(R 24 ) wherein R 20 is hydrogen, methyl or benzyl and R 24 is
hydrogen or methyl;
RlOa is methoxy and R 10b is hydrogen; and
X and Y taken together are oxo.
10
15
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26. A compound of the formula:
R 9
R -S(0) 2 0„ J
CHgO
VI
wherein R is F;
R 1 is hydrogen, a hydroxy protecting group, loweralkyl or phenyl-substituted
loweralkyl;
10
R 2 is hydrogen and R 3 is hydroxy or protected hydroxy or R 2 and R 3 taken
together are oxo;
R 4 is hydrogen or phenyl-substituted loweralkyl and R 5 is hydroxy or protected
15 hydroxy or R5 is hydrogen or phenyl-substituted loweralkyl and R 4 is hydroxy or
protected hydroxy or R 4 and R 5 taken together are oxo;
R 6 is hydrogen or phenyl-substituted loweralkyl and R 7 is hydrogen, hydroxy or
protected hydroxy or R 7 is hydrogen or phenyl-substituted loweralkyl and R 6 is
20 hydroxy or protected hydroxy or R 6 and R 7 taken together are
(1) oxo,
(2) diazo,
(3) =CH 2
(4) -0-(CH 2 ) 2 -0-,
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25 (5) -S-(CH 2 ) 2 -S-,
(6) -0-(CH 2 ) 3 -0-,
(7) -S-(CH 2 ) 3 -S-,
(8) =N-OR 20 wherein R 20 is hydrogen, loweralkyl, alkenyl, cycloalkyl,
cycloalkenyl, bicycloalkenyl, aryl, arylalkyl, heterocyclic or
30 heterocyclicalkyl, each of which is optionally substituted with loweralkyl,
halogen, hydroxy, aryl or heterocyclic; or
(9) =N-N(R 21 )(R 22 ) wherein R 21 and R 22 are independently selected
from hydrogen, loweralkyl, aryl, arylalkyl, heterocyclic and
heterocyclicalkyl;
35
R 9 is hydrogen;
R 10a is hydrogen and R 10b is hydrogen, hydroxy, protected hydroxy, alkoxy,
alkenyl, alkenyloxy, halogen or -SR 28 wherein R 28 is independently defined as
40 above or R 10b is hydrogen and R 10a is hydrogen, hydroxy, protected hydroxy,
alkoxy, alkenyl, alkenyloxy, halogen or -SR 28 wherein R 28 is independently
defined as above or R 10a and R 10b are both alkoxy or -SR 28a wherein R 28a is
loweralkyl, aryl or heterocyclic or R 10a and R 10b taken together are oxo; and
45 X is hydrogen and Y is hydrogen, hydroxy or protected hydroxy or Y is hydrogen
and X is hydroxy or protected hydroxy or X and Y taken togehter are oxo;
or a pharmaceutically acceptable salt, ester, amide or prodrug thereof.
50
27. A compound according to Claim 26 wherein
R is F;
R 1 is methyl;
R 2 is hydrogen and R 3 is hydroxy;
5 R 4 is hydrogen and R 5 is hydroxy or R 5 is hydrogen and R 4 is hydroxy or R 4 and
R 5 taken together are oxo;
R 6 and R 7 are defined as above;
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R 10a is hydrogen, methoxy or fluoro and R 10b is hydrogen; and
X and Y taken together are oxo.
10
28. A compound according to Claim 26 wherein
RisF;
R 1 is methyl;
R 2 is hydrogen and R 3 is hydroxy;
5 R 4 is hydrogen and R 5 is hydroxy or R 5 is hydrogen and R 4 is hydroxy or R 4 and
R 5 taken together are oxo;
R 6 and R 7 taken together are
(1) oxo,
(2) =N-OR 20 wherein R 20 is hydrogen, loweralkyl, alkenyl, cycloalkyl,
10 cycloalkenyl, bicycloalkenyl, aryl, arylalkyl, heterocyclic or
heterocyclicalkyl, each of which is optionally substituted with loweralkyl,
halogen, hydroxy, aryl or heterocyclic; or
(3) =N-N(R 21 )(R 22 ) wherein R 21 and R 22 are independently selected
from hydrogen^ loweralkyl, aryl, arylalkyl, heterocyclic and
15 heterocyclicalkyl;
RlOa i s hydrogen, methoxy or fluoro and R 10b is hydrogen; and
X and Y taken together are oxo.
29. A compound according to Claim 26 wherein
Ris F;
R 1 is methyl;
R 2 is hydrogen and R 3 is hydroxy;
5 R 4 and R^ taken together are oxo;
R 6 and R 7 taken together are
(1) oxo,
(2) =N-OR 20 wherein R 20 is hydrogen, loweralkyl, alkenyl, cycloalkyl,
cycloalkenyl, bicycloalkenyl, aryl, arylalkyl, heterocyclic or
10 heterocyclicalkyl, each of which is optionally substituted with loweralkyl,
halogen, hydroxy, aryl or heterocyclic; or
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(3) =N-N(R 21 )(R 22 ) wherein R 21 and R 22 are independently selected
from hydrogen, loweralkyl, aryl, arylalkyl, heterocyclic and
heterocyclicalkyl;
15 R 10a is methoxy and R 10b is hydrogen; and
X and Y taken together are oxo.
30. A compound according to Claim 26 wherein
Ris F;
R 1 is methyl;
R 2 is hydrogen and R 3 is hydroxy;
5 R 4 and R 5 taken together are oxo;
R 6 and R 7 taken together are oxo;
R 10a is methoxy and R 10b is hydrogen; and
X and Y taken together are oxo.
31. A compound of the formula:
VII
5 wherein R 1 is hydrogen, a hydroxy protecting group, loweralkyl or phenyl-
substituted loweralkyl;
R 2 is hydrogen and R 3 is hydroxy or protected hydroxy or R 2 and R 3 taken
together are oxo;
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10
R 4 is hydrogen or phenyl-substituted loweralkyl and R 5 is hydroxy or protected
hydroxy or R 5 is hydrogen or phenyl-substituted loweralkyl and R 4 is hydroxy or
protected hydroxy or R 4 and R 5 taken together are oxo;
15 R 6 is hydrogen or phenyl-substituted loweralkyl and R 7 is hydrogen, hydroxy or
protected hydroxy or R 7 is hydrogen or phenyl-substituted loweralkyl and R 6 is
hydroxy or protected hydroxy or R 6 and R 7 taken together are
(1) oxo,
(2) diazo,
20 (3) =CH 2
(4) -0-(CH 2 ) 2 -0,
(5) -S-(CH 2 ) 2 -S-,
(6) -0-(CH 2 ) 3 -0-,
(7) -S-(CH 2 ) 3 -S-,
25 (8) =N-OR 20 wherein R 20 is hydrogen, loweralkyl, alkenyl, cycloalkyl,
cycloalkenyl, bicycloalkenyl, aryl, arylalkyl, heterocyclic or
heterocyclicalkyl, each of which is optionally substituted with loweralkyl,
halogen, hydroxy, aryl or heterocyclic; or
(9) =N-N(R 21 )(R 22 ) wherein R 21 and R 22 are independently selected
30 from hydrogen, loweralkyl, aryl, arylalkyl, heterocyclic and
heterocyclicalkyl;
R8
is
(1) -0(CH 2 )iC(0)OR 20 wherein i is one or two and R 20 is independently
35 defined as above,
(2) -0(CH 2 )jC(0)N(R 24 )(R 2 5) wherein i is one or two and R 24 and R25
are independently selected from
(a) hydrogen,
(b) loweralkyl,
40 (c) alkenyl,
(d) alkynyl,
(e) cycloalkyl,
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(f) substituted loweralkyl, substituted alkenyl, substituted alkynyl
or substituted cycloalkyl wherein the loweralkyl group, the
45 alkenyl group, the alkynyl group or the cycloalkyl group is
substituted by one or two substituents independently selected from
(i) hydroxy,
(ii) -COOH,
(iii) -CN,
50 (iv) -Q-loweralkyl, -Q-aryl, -Q-(arylalkyl), -Q-heterocyclic
or -Q-(heterocyclicalkyl) wherein Q is -0-, -S-, -S(O)-,
-S(0) r , -C(O)-, -OC(O)-, -C(0)0-, -C(0)C(0)-0-,
-0-C(0)C(0)-, -C(0)NH-, -NHC(O)-, -OC(0)NH-,
-NHC(0)0-, -NH-C(0)-NH-, -S(0) 2 NH-, -NHS(0) 2 -,
55 -N(R27)., -C(NR27)NHNH- and -NHNHC(NR 27 )- wherein
R 27 is hydrogen, loweralkyl, aryl or heterocyclic,
(v) cycloalkyl,
(vi) aryl,
(vii) heterocyclic,
60 *(viii) -N(R28)(R29) wherein R 28 and R 2 9 are independently
selected from hydrogen, loweralkyl, hydroxyalkyl, aryl
and heterocyclic,
(ix) guanidino,
(x) -S(0) 2 R n wherein R 11 is loweralkyl, aryl or arylalkyl,
65 (xi) -OS(0) 2 R 11 wherein R 11 is defined as above,
(xii) -S0 3 H,
(xiii) -S(0) 2 NH 2 ,
(xiv) -SR 28 wherein R 28 is defined as above,
(xv) halogen,
70 (xvi) oxo and
(xvii) epoxy;
(g) aryl,
(h) heterocyclic,
(i) -NHC(0)-0-loweralkyl,
75 (j) -NHC(0)-aryl,
(k) -NHC(0)-heterocyclic and
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(1) loweralkyl substituted by -OC(0)-R f wherein R f is
carboxyalkyl
or -N(R 24 )(R 2 5) taken together form a nitrogen-containing
80 heterocyclic group,
(3) -0(CH 2 ) i C(0)N(OR24)(R25) wherein i, R 2 * and R25 are defined as
above,
(4) -0(CH 2 ) i C(0)N(R24)(N(R24) (R 25 )) wh erein i, R24 and R 25 ^
defined as above,
85 (5) -0(CH 2 )jNHC(0)N(R24)(R25) whe rein i, R24 an d R25 are defined as
above,
(6) -(CH 2 ) i NHC(0)N(OR24)(R25 ) wherein i, R24 and R25 are defined as
above or
(7) -(CH 2 ) i NHC(0)N(R24)( N (R24)(R25)) whe rein i, R24 an d R25 are
90 defined as above;
R 9 is hydrogen;
RlOa i s hydrogen and R 1 ^ is hydrogen, hydroxy, protected hydroxy, alkoxy,
95 alkenyl, alkenyloxy, halogen or -SR 28 wherein R 28 i s independently defined as
above or R*0b i s hydrogen and R l ^a. - 1S hydrogen, hydroxy, protected hydroxy,
alkoxy, alkenyl, alkenyloxy, halogen or -SR 28 wherein R 28 is independently
defined as above or R 10a and RiOb are both alkoxy or -SR 28 a wherein R 2 8a i s
loweralkyl, aryl or heterocyclic or R^a an d RlOb taksn together are oxo; and
100
X is hydrogen and Y is hydrogen, hydroxy or protected hydroxy or Y is hydrogen
and X is hydroxy or protected hydroxy or X and Y taken togehter are oxo;
or a pharmaceutically acceptable salt, ester, amide or prodrug thereof.
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32. A compound according to Claim 3 1 wherein
R 1 is methyl;
R 2 is hydrogen and R 3 is hydroxy;
R 4 is hydrogen and R 5 is hydroxy or R 5 is hydrogen and R 4 is hydroxy or R 4 and
5 R 5 taken together are oxo;
R 6 and R 7 are defined as above;
R8 is defined as above;
R 9 is hdyrogen;
RlOa j s hydrogen, methoxy or fluoro and R 10b is hydrogen; and
10 X and Y taken together are oxo.
33. A compound according to Claim 3 1 wherein
R 1 is methyl;
R 2 is hydrogen and R 3 is hydroxy;
R 4 is hydrogen and R 5 is hydroxy or R 5 is hydrogen and R 4 is hydroxy or R 4 and
5 R 5 taken together are oxo;
R 6 and R 7 taken together are
(1) oxo,
(2) =N-OR 20 wherein R 20 is hydrogen, loweralkyl, alkenyl, cycloalkyl,
cycloalkenyl, bicycloalkenyl, aryl, arylalkyl, heterocyclic or
10 heterocyclicalkyl, each of which is optionally substituted with loweralkyl,
halogen, hydroxy, aryl or heterocyclic; or
(3) =N-N(R 2 *)(R 22 ) wherein R 2 * and R 22 are independendy selected
from hydrogen, loweralkyl, aryl, arylalkyl, heterocyclic and
heterocyclicalkyl;
15 R8 is
(1) -0(CH 2 ) i C(0)N(R 24 )(R 2 5) wherein i is one or two and R 24 and R 2 $
are independently selected from
(a) hydrogen,
(b) loweralkyl,
20 (c) alkenyl,
(d) alkynyl,
(e) cycloalkyl,
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(f) substituted loweralkyl, substituted alkenyl, substituted alkynyl
or substituted cycloalkyl wherein the loweralkyl group, the
alkenyl group, the alkynyl group or the cycloalkyl group is
substituted by one or two substituents independently selected from
(i) hydroxy,
(ii) -COOH,
(iii) -CN,
(iv) -Q-loweralkyl, -Q-aryl, -Q-(arylalkyl), -Q-heterocyclic
or -Q-(heterocyclicalkyl) wherein Q is -O-, -S-, -S(O)-,
-S(0) 2 -, -C(O)-, -OC(O)-, -C(0)0-, -C(0)C(0)-0-,
-0-C(0)C(0)-, -C(0)NH-, -NHC(O)-, -OC(0)NH-,
-NHC(0)0-, -NH-C(0)-NH-, -S(0) 2 NH-, -NHS(0) 2 -,
-N(R27)-, -C(NR27)NHNH- and -NHNHC(NR27). wherein
R 27 is hydrogen, loweralkyl, aryl or heterocyclic,
(v) cycloalkyl,
(vi) aryl,
(vii) heterocyclic,
(viii) -N(R28)(R29) wherein R28 and R29 are independently
selected from hydrogen, loweralkyl, hydroxyalkyl, aryl
and heterocyclic,
(ix) guanidino,
(x) -S(0) 2 R n wherein R 11 is loweralkyl, aryl or arylalkyl,
(xi) -OS(0) 2 RH wherein R" is defined as above,
(xii) -SO3H,
(xiii) -S(0) 2 NH 2 ,
(xiv) -SR28 wherein R28 i s defined as above,
(xv) halogen,
(xvi) oxo and
(xvii) epoxy;
(g) aryl,
(h) heterocyclic,
(i) -NHC(0)-0-loweralkyl,
(j) -NHC(0)-aryl,
(k) -NHC(0)-heterocyclic and
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(1) loweralkyl substituted by -OC(0)-R f wherein R f is
carboxyalkyl
or -N(R 24 )(R 25 ) taken together form a nitrogen-containing
60 heterocyclic group or
(2) -0(CH 2 )jC(0)N(OR24)(R25) wherein i, R24 and R25 are defined as
above,
R 9 is hydrogen;
RlOa i s hydrogen, methoxy or fluoro and R 10b is hydrogen; and
65 X and Y taken together are oxo.
34. A compound according to Claim 31 wherein
R 1 is methyl;
R 2 is hydrogen and R 3 is hydroxy;
R 4 and R 5 taken together are oxo;
5 R6 and R 7 taken together are
(1) oxo,
(2) =N-OR 20 wherein R 20 is hydrogen, loweralkyl, alkenyl, cycloalkyl,
cycloalkenyl, bicycloalkenyl, aryl, arylalkyl, heterocyclic or
heterocyclicalkyl, each of which is optionally substituted with loweralkyl,
10 halogen, hydroxy, aryl or heterocyclic; or
(3) =N-N(R 2 1)(R 22 ) wherein R21 and R 2 2 are independently selected
from hydrogen, loweralkyl, aryl, arylalkyl, heterocyclic and
heterocyclicalkyl;
R8 is -0(CH 2 ) i C(0)N(R24)(R25) wherein i is one or two and R24 and R25 are
15 independently selected from
(a) hydrogen,
(b) loweralkyl,
(c) alkenyl,
(d) alkynyl,
20 (e) cycloalkyl,
(f) substituted loweralkyl, substituted alkenyl, substituted alkynyl
or substituted cycloalkyl wherein the loweralkyl group, the
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alkenyl group, the alkynyl group or the cycloalkyl group is
substituted by one or two substituents independently selected from
25 (i) hydroxy,
(ii) -COOH,
(iii) -CN,
(iv) -Q-loweralkyl, -Q-aryl, -Q-(arylalkyl), -Q-heterocyclic
or -Q-(heterocyclicalkyl) wherein Q is -O-, -S-, -S(O)-,
30 -S(0) 2 -, -C(O)-, -OC(O)-, -C(0)0-, -C(0)C(0)-0-,
-0-C(0)C(0)-, -C(0)NH-, -NHC(O)-, -OC(0)NH-,
-NHC(0)0-, -NH-C(0)-NH-, -S(0) 2 NH-, -NHS(OJ 2 -,
-N(R27)_, -C(NR27)NHNH- and -NHNHC(NR 27 )- wherein
R 27 is hydrogen, loweralkyl, aryl or heterocyclic,
35 (v) cycloalkyl,
(vi) aryl,
(vii) heterocyclic,
(viii) -N(R 2 8)(R29) wherein R28 and R 29 are independently
selected from hydrogen, loweralkyl, hydroxyalkyl, aryl
40 and heterocyclic,
(ix) guanidino,
(x) -S(0) 2 R n wherein R 11 is loweralkyl, aryl or arylalkyl,
(xi) -OS(0) 2 R n wherein R 11 is defined as above,
(xii) -S0 3 H,
45 (xiii) -S(0) 2 NH 2 ,
(xiv) -SR 28 wherein R 28 is defined as above,
(xv) halogen,
(xvi) oxo and
(xvii) epoxy;
50 (g) aryl,
(h) heterocyclic,
(i) -NHC(0)-0-loweralkyl,
(j) -NHC(0)-aryl,
(k) -NHC(0)-heterocyclic and
55 (1) loweralkyl substituted by -OC(0)-R f wherein R f is
carboxyalkyl
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or -N(R 24 )(R 25 ) taken together form a nitrogen-containing
heterocyclic group,
R 9 is hydrogen;
60 R 10a is methoxy and R 10b is hydrogen; and
X and Y taken together are oxo.
35. A compound according to Claim 31 wherein
R 1 is methyl;
R 2 is hydrogen and R 3 is hydroxy;
R 4 and R 5 taken together are oxo;
5 R 6 and R 7 taken together are
(1) oxo,
(2) =N-OR 20 wherein R 20 is hydrogen, loweralkyl, alkenyl, cycloalkyl,
cycloalkenyl, bicycloalkenyl, aryl, arylalkyl, heterocyclic or
heterocyclicalkyl, each of which is optionally substituted with loweralkyl,
10 halogen, hydroxy, aryl or heterocyclic; or
(3) =N-N(R 21 )(R 22 ) wherein R 21 and R 22 are independently selected
from hydrogen, loweralkyl, aryl, arylalkyl, heterocyclic and
heterocyclicalkyl;
R8 is -0(CH 2 ) i C(0)N(OR24)(R25 ) wherein i is one or two and R 24 and R 2 $ are
15 independently selected from
(a) hydrogen,
(b) loweralkyl,
(c) alkenyl,
(d) alkynyl,
20 (e) cycloalkyl,
(f) substituted loweralkyl, substituted alkenyl, substituted alkynyl
or substituted cycloalkyl wherein the loweralkyl group, the
alkenyl group, the alkynyl group or the cycloalkyl group is
substituted by one or two substituents independently selected from
25 (i) hydroxy,
(ii) -COOH,
(iii) -CN,
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(iv) -Q-loweralkyl, -Q-aryl, -Q-(arylalkyl), -Q-heterocyclic
or -Q-(heterocyclicalkyl) wherein Q is -O-, -S-, -S(O)-,
30 -S(0) 2 -, -C(O)-, -OC(O)-, -C(0)0-, -C(0)C(0)-0-,
-0-C(0)C(0)-, -C(0)NH-, -NHC(O)-, -OC(0)NH-,
-NHC(0)0-, -NH-C(0)-NH-, -S(0) 2 NH-, -NHS(0) 2 -,
-N(R 27 )-, -C(NR 27 )NHNH- and -NHNHC(NR 27 )- wherein
R 27 is hydrogen, ioweralkyl, aryl or heterocyclic,
35 (v) cycloalkyl,
(vi) aryl,
(vii) heterocyclic,
(viii) -N(R 28 )(R 29 ) wherein R 28 and R 29 are independently
selected from hydrogen, Ioweralkyl, hydroxyalkyl, aryl
40 and heterocyclic,
(ix) guanidino,
(x) -S(0) 2 R n wherein R 11 is Ioweralkyl, aryl or arylalkyl,
(xi) -OSCO^R 11 wherein R» is defined as above,
(xii) -S0 3 H,
45 (xiii) -S(0) 2 NH 2 ,
(xiv) -SR 28 wherein R 28 is defined as above,
(xv) halogen,
(xvi) oxo and
(xvii) epoxy;
50 (g) aryl,
(h) heterocyclic,
(i) -NHC(0)-0-loweralkyl,
(j) -NHC(0)-aryl,
(k) -NHC(0)-heterocyclic and
55 (1) Ioweralkyl substituted by -OC(0)-R f wherein R f is
carboxyalkyl
or -N(R 24 )(R 25 ) taken together form a nitrogen-containing
heterocyclic group,
R 9 is hydrogen;
60 R 10a is methoxy and R 10b is hydrogen; and
X and Y taken together are oxo.
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36. A compound according to Claim 31 wherein
R 1 is methyl;
R 2 is hydrogen and R 3 is hydroxy;
R 4 and R 5 taken together are oxo;
5 R6 and R 7 taken together are oxo;
R 8 is -0(CH 2 ) i C(0)N(OR 24 )(R 25 ) wherein i is one or two and R 24 is hydrogen,
loweralkyl or arylalkyl and R 25 is hydrogen, loweralkyl or cycloalkyl;
R 9 is hydrogen;
R 10a is methoxy and R 10b is hydrogen; and
10 X and Y taken together are oxo.
37. A pharmaceutical composition for immunomodulatory treatment
comprising a compound according to Claim 1 in combination with a
pharmaceutically acceptable carrier.
38. A method of immunomodulatory treatment comprising
administering to a mammal in need of such treatment a therapeutically effective
amount of a compound according to Claim 1.
39. A pharmaceutical composition for immunomodulatory treatment
comprising a compound according to Claim 6 in combination with a
pharmaceutically acceptable carrier.
40. A method of immunomodulatory treatment comprising
administering to a mammal in need of such treatment a therapeutically effective
amount of a compound according to Claim 6.
41. A pharmaceutical composition for immunomodulatory treatment
comprising a compound according to Claim 1 1 in combination with a
pharmaceutically acceptable carrier.
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42. A method of immunomodulatory treatment comprising
administering to a mammal in need of such treatment a therapeutically effective
amount of a compound according to Claim 11.
43. A pharmaceutical composition for immunomodulatory treatment
comprising a compound according to Claim 16 in combination with a
pharmaceutically acceptable carrier.
44. A method of immunomodulatory treatment comprising
administering to a mammal in need of such treatment a therapeutically effective
amount of a compound according to Claim 16.
45. A pharmaceutical composition for immunomodulatory treatment
comprising a compound according to Claim 21 in combination with a
pharmaceutically acceptable carrier.
46. A method of immunomodulatory treatment comprising
administering to a mammal in need of such treatment a therapeutically effective
amount of a compound according to Claim 21.
47. A pharmaceutical composition for immunomodulatory treatment
comprising a compound according to Claim 31 in combination with a
pharmaceutically acceptable carrier.
48. A method of immunomodulatory treatment comprising
administering to a mammal in need of such treatment a therapeutically effective
amount of a compound according to Claim 31.
10
UN 1 bKlN/ViiOiNAL. SJbAK^tt Ktl-UKl
Intemat Application No
PCT/US 94/12777
A. CLASSIFICATION OF SUBJECT MATTER
IPC 6 C07D498/18 A61K31/445 A61K31/395 //(C07D498/18.311 :00,
221:00)
According to International Patent Classification (IPC) or to both national classification and IPC
B. FIELDS SEARCHED
Minimum documentation searched (classification system followed by classification symbols)
IPC 6 C07D A61K
Documentation searched other than minimum documentation to the extent that such documents are included in the fields searched
Electronic data base consulted during the international search (name of data base and, where practical, search terms used)
C. DOCUMENTS CONSIDERED TO BE RELEVANT
Category " Citation of document, with indication, where appropriate, of the relevant passages
Relevant to claim No.
WO, A, 93 18043 (AMERICAN HOME PROD ) 16
September 1993
see claim 1
WO, A, 93 11130 (SMITHKLINE BEECHAM PLC ) 10
June 1993
see claim 1
WO, A, 92 05179 (AMERICAN HOME PROD ) 2
April 1992
see claim 1
WO, A, 92 21341 (PFIZER ) 10 December 1992
1-5,
16-20,37
1-37
1-37
1-5,
16-25,
31-37
see claim 1
-/—
Further documents are listed in the continuation of box C.
Patent family members are listed in annex.
° Special categories of ated documents :
*A' document defining the general state of the art which is not
considered to be of particular relevance
*E" earlier document but published on or after the international
filing date
"L" document which may throw doubts on priority claimfs) or
which is ated to establish the publication date of another
citation or other special reason (as specified)
"O" document referring to an oral disclosure, use, exhibition or
other means
"P" document published prior to the international filing date but
later than the priority date claimed
"T" later document published after the international filing date
or priority date and not in conflict with the application but
cited to understand the principle or theory underlying the
invention
'X* document of particular relevance; the claimed invention
cannot be considered novel or cannot be considered to
involve an inventive step when the document is taken alone
' Y" document of particular relevance; the claimed invention
cannot be considered to involve an inventive step when the
document is combined with one or more other such docu-
ments, such combination being obvious to a person skilled
in the art.
"&" document member of the same patent family
Date of the actual completion of the international search
4 April 1995
Date of mailing of the international search report
- 3. 05. 95
Name and mailing address of the ISA
European Patent Office, P.B. 5818 Patentlaan 2
NL - 2280 HV Rijswijk
Tel. ( + 31-70) 340-2040, Tx. 31 651 epo nl,
Fax: ( + 31-70) 340-3016
Authorized officer
Stellmach, J
Form PCT/ISA/210 (tecond fheet) (July 1992)
page 1 of 3
IN 1 fcKNA i iUiNAL StiAK^n KCfUK 1
Internat Application No
PCT/US 94/12777
C(Continuation) DOCUMENTS CONSIDERED TO BE RELEVANT
Category *
Citation of document, with indication, where appropriate, of the relevant passages
Relevant to claim No.
X
US, A, 5 258 389 (GOULET MARK ET AL) 2
November 1993
see claim 1
1-37
X
US, A, 5 260 300 (HU DAVID C ) 9 November
1993
* & WO-A-94/11 380 *
see claim 1
1-37
X
US, A, 5 262 423 (KAO WENLING ) 16 November
1993
* & WO-A-94/10176 *
see claim 1
1-37
X
US, A, 5 233 036 (HUGHES PHILIP F ) 3 August
1993
see claim 1
1-37
X
US, A, 5 151 413 (CAUFIELD CRAIG E ET AL) 29
September 1992
see claim 1
1-37
X
US, A, 5 100 883 (SCHIEHSER GUY A ) 31 March
1992
see claim 1
1-37
Y
EP.A.O 515 140 (AMERICAN HOME PROD ) 25
November 1992
see claim 1
1-37
Y
EP,A,0 509 795 (AMERICAN HOME PROD ) 21
October 1992
see claim 1
1-37
Y
EP.A.O 507 556 (AMERICAN HOME PROD ) 7
October 1992
see claim 1
1-37
Y
EP.A.O 470 804 (AMERICAN HOME PROD ) 12
February 1992
see claim 1
16
Y
EP,A,0 429 436 (UNIV KANSAS ) 29 May 1991
see claim 1
1-37
P,X
EP.A.O 593 227 (AMERICAN HOME PROD ) 20
April 1994
see claim 1
1-37
P,X
W0, A, 94 02137 (SMITHKLINE BEECHAM CORP
;H0LT DENNIS ALAN (US); LUENGO JUAN
IGNALij i rebruary iay*r
see claim 1
1-37
Form PCT,1SA'210 (conUnumtion of f«and «he«t) (July 1993)
page 2 of 3
INTERNATIONAL SEARCH REPORT
Internet ' Application No
PCT/US 94/12777
CfConttnuaUon) DOCUMENTS CONSIDERED TO BE RELEVANT
Category °
Citation of document, with indication, where appropriate, of the relevant passages
Relevant to claim No.
p,x
p,x
p,x
p,x
WO, A, 94 02485 (SMITHKLINE BEECHAM CORP
;H0LT DENNIS ALAN (US); LUENGO JUAN
IGNACI) 3 February 1994
see claim 1
WO, A, 94 04540 (AMERICAN HOME PROD ) 3
March 1994
see claim 1
WO, A, 94 09010 (SAND0Z AG ;SAND0Z AG (OE) ;
SAND0Z LTD (CH); COTTENS SYLVAIN (CH); )
28 April 1994
see claim 1
W0, A, 94 02136 (SMITHKLINE BEECHAM CORP
; LUENGO JUAN IGNACI0 (US)) 3 February 1994
see claim 1
1-37
1-37
1-37
1-37
'l
Form PCT7ISA/210 (continuation of recond sheet) (July 1992)
page 3 of 3
INTERNATIONAL SEARCH REPORT
Intern^onai application No.
PCT/US 94/ 12777
Box I Observations where certain claims were found unsearchable (Continuation of item I of first sheet)
This international search report has not been established in respect of certain claims under Article 17(2)(a) for the following reasons:
1. Claims Nos.:
because they relate to subject matter not required to be searched by this Authority, namely:
Although claims 38-48 are directed to a method of treatment of the human/
animal body (Rule 39.1.(iv), the search has been carried out and based on
the alleged effects of the compounds.
2 ' ^ beaSsVthey relate to parts of the international application that do not comply with the prescribed requirements to such
an extent that no meaningful international search can be carried out, specifically:
be^se'they are dependent claims and are not drafted in accordance with the second and third sentences of Rule 6.4(a).
Box II Observations where unity of invention is lacking (Continuation of item 2 of first sheet)
This International Searching Authority found multiple inventions in this international application, as follows:
1 . Q^j As all required additional search fees were timely paid by the applicant, this international search report covers all
searchable claims.
2. [""I As all searchable claims could be searches without effort justifying an additional fee, this Authority did not invite payment
of any additional fee.
3. A.s only some of the required additional search fees were timely paid by the applicant,
' 1 covers only those claims for which fees were paid, specifically claims Nos.:
this international search report
4 I I No required additional search fees were timely paid by the applicant. Consequently, this international search report is
1 1 restricted to the invention first mentioned in the claims; it is covered by claims Nos.:
Remark on Protest [^] The additional search fees were accompanied by the applicant's protest.
| | No protest accompanied the payment of additional search fees.
Form P<nVISAf210 (continuation of first sheet (1)) (July 1992)
IIYlKKNATiONAL SEARCH REPORT
Information on patent family members
Internat Application No
PCT/US 94/12777
Patent document
Publication
Patent family
Publication
cited in search report
date
member(s)
date
WO-A-9318043
16-09-93
US-A-
5177203
05-01-93
1 IC — A-
io _ uy-y4
US-A-
5260299
HQ— 1 1 —Ol
uy-n-yo
WO-A-9311130
10-06-93
AU-A-
2954392
28-06-93
• EP-A-
0621865
JP-T-
7501804
oo no nc
WO-A-9205179
02-04-92
AU-B-
653175
oo nn nvi
22-09-94
AU-A-
8659991
i c nil no
15-04-92
CA-A-
2051781
or* no no-
20-03-92
EP-A-
0549727
07-07-93
HU-A-
65763
oo n "7 ftji
28-07-94
Jr- 1 -
OT n 1 CLA
27-01-94
US-A-
5358944
*>C 1 f\ ClA
25-10-94
US-A-
5378696
03-01-95
US-A-
5221670
22-06-93
OAF 1 700
2Ubl/o2
on no no
29-03-92
US-A-
5130307
14-07-92
WO-A-9221341
10-12-92
CA-A-
2102116
01-12-92
EP-A-
0586512
16-03-94
JP-T-
6502659
24-03-94
US-A-5258389
02-11-93
N0NE
U5-A-b2o0300
09-11-93
AU-B-
5322094
n n »r\ /* n m
08-06-94
WO-A-
9411380
26-05-94
US-A-5262423
16-11-93
AU-B-
f» A A A A A ja
5322294
24-05-94
WO-A-
9410176
11-05-94
US-A-5233036
03-08-93
N0NE
US-A-5151413
29-09-92
NONE
US-A-5100883
31-03-92
NONE
EP-A-0515140
25-11-92
US-A-
5118677
02-06-92
AU-B-
641319
16-09-93
Form PCT/ISA/210 (patent family annex) (July 1992)
page 1 of 3
1NTUKNAT1UNAL, SHiARCH REPORT
Iniormaaon on patent family members
Internal Application No
PCT/US 94/12777
Patent document
cited in search report
Publication
date
Patent family
member(s)
Publication
date
EP-A-0515140 AU-A- 1637892 26-11-92
JP-A- 5148271 15-06-93
NZ-A- 242778 26-07-94
EP-A-0509795
21-10-92
US-A-
5118678
02-06-92
US-A-
5194447
16-03-93
AU-B-
642592
21-10-93
AU-A-
1488092
22-10-92
JP-A-
5112573
07-05-93
NZ-A-
242367
26-07-94
CA-A-
2065791
19-08-93
US-A-
5262424
16-11-93
EP-A-0507556 07-10-92 US-A- 5120842 09-06-92
AU-A- 1389392 08-10-92
JP-A- 5078377 30-03-93
EP-A-0470804 12-02-92 US-A- 5023263 11-06-91
AU-B- 639126 15-07-93
AU-A- 8162491 13-02-92
CA-A- 2048540 10-02-92
GB-A.B 2246776 12-02-92
JP-A- 4230687 19-08-92
EP-A-0429436 29-05-91
US-A-
4650803
17-
-03-
-87
AU-B-
583439
27-
-04-
-89
AU-A-
6608086
11-
-06-
-87
CA-A-
1273920
11-
-09-
-90
CA-A-
1312076
29-
-12-
-92
DE-A-
3684574
30-
-04-
-92
DK-B-
169409
24-
-10-
-94
EP-A.B
0227355
Ol-
-07-
-87
GB-A.B
2183647
IO-
-06-
-87
JP-B-
6070066
07-
-09-
-94
JP-A-
62215592
22-
-09-
-87
JP-A-
6263765
20-
-09-
-94
KR-B-
9404072
11
-05-
-94
KR-B-
9404073
11
-05-
-94
EP-A-0593227 20-04-94 US-A- 5302584 12-04-94
Form PCT/ISA/310 (piunt family annex) (July 1992)
page 2 of 3
INTERNATIONAL SEARCH REPORT
Internac Application No
PCT/US 94/12777
Patent document
cited in search report
Publication
date
Patent family
member(s)
Publication
date
All-R-
28-04-94
BR-A-
9304211
07-06-94
FI-A-
934501
14-04-94
r a-A-
LlUOUDO
14-04-94
CN-A-
1091135
24-08-94
JP-A-
6211870
02-08-94
UO U£ 3"t
AU-B-
4680193
1*T Wfc. 3t
CN-A-
1087912
15-06-94
WO-A-9402485
w£. -7*T
All— R-
AU D
TDOUU7J
14-02-94
at Uh «?"T
CN-A-
1087911
15-06-94
A*S WW JT
WO-A-9404540
03-03-94
AU-B-
5007193
15-03-94
US-A-
5302600
12-04-94
US-A-
5256790
26-10-93
WO-A-9409010
28-04-94
AU-B-
4819293
09-05-94
WO-A-9402136
03-02-94
AU-B-
CN-A-
4679993
1087913
14- 02-94
15- 06-94
0
Form PCT.1SA/310 (patent famUy annex) (July 1993)
page 3 of 3
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